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SECOND EDITION 




Neurology in 
Clinical Medicine 



EDITOR 

STEPHEN L. HAUSER 

ASSOCIATE EDITOR 

SCOTT ANDREW JOSEPHSON 





VjjrJSfflL-,,.. 



m 





Second Edition 

^HARRISON'S 

Neurology in 
Clinical Medicine 






Derived from Harrison's Principles of Internal Medicine, 17th Edition 



Editors 



ANTHONY S. FAUCI, md 

Chief, Laboratory of Immunoregulation; 

Director, National Institute of Allergy and Infectious Diseases, 

National Institutes of Health, Bethesda 



EUGENE BRAUNWALD, md 

Distinguished Hersey Professor of Medicine, 

Harvard Medical School; Chairman, TIMI Study Group, 

Brigham and Women's Hospital, Boston 



DENNIS L. KASPER, md 

William Ellery Channing Professor of Medicine, Professor of 
Microbiology and Molecular Genetics, Harvard Medical School; 
Director, Channing Laboratory, Department of Medicine, 
Brigham and Women's Hospital, Boston 



DAN L. LONGO, md 

Scientific Director, National Institute on Aging, 
National Institutes of Health, 
Bethesda and Baltimore 



STEPHEN L. HAUSER, md 

Robert A. Fishman Distinguished Professor and Chairman, 
Department of Neurology, University of California, San Francisco 



J. LARRY JAMESON, md, PhD 

Professor of Medicine; 

Vice President for Medical Affairs 

and Lewis Landsberg Dean, 

Northwestern University Feinberg 

School of Medicine, Chicago 



JOSEPH LOSCALZO, md, PhD 

Hersey Professor of Theory and Practice of Medicine, 

Harvard Medical School; Chairman, Department of Medicine; 

Physician-in-Chief, Brigham and Women's Hospital, Boston 




Second Edition 



HARRISON'S 

Neurology in 
Clinical Medicine 



Editor 
Stephen L. Hauser, MD 

Robert A. Fishman Distinguished Professor and Chairman, 
Department of Neurology, University of California, San Francisco 



Associate Editor 
Scott Andrew Josephson, MD 

Assistant Clinical Professor of Neurology, 
University of California, San Francisco 



Medical 



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Milan New Delhi San Juan Seoul Singapore Sydney Toronto 



The McGraw-Hill Companies 



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Raymond D. Adams, MD 
1911-2008 



For Ray Adams, editor of Harrison's Principles of Internal Medicine for more than three decades. 

A mentor who taught by example, 

a colleague who continues to inspire, and 

a friend who is deeply missed. 

Stephen L. Hauser, MD, for the Editors of Harrison's 



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CONTENTS 



Contributors xi 

Preface xv 

SECTION I 
INTRODUCTION TO NEUROLOGY 

1 Approach to the Patient with 

Neurologic Disease 2 

Daniel H. Lowenstein, Joseph B. Martin, 
Stephen L. Hauser 

2 Neuroimaging in Neurologic Disorders 11 

William P. Dillon 

3 Electrodiagnostic Studies of Nervous 
System Disorders: EEG, Evoked Potentials, 

and EMG 24 

Michael]. Aminoff 

4 Lumbar Puncture 33 

Elizabeth Robbins, Stephen L. Hauser 

SECTION II 

CLINICAL MANIFESTATIONS OF 

NEUROLOGIC DISEASE 

5 Pain: Pathophysiology and Management 40 

Howard L. Fields, Joseph B. Martin 

6 Headache 50 

Peter J. Goadsby, Neil H. Raskin 

7 Back and Neck Pain 70 

John W. Engstrom 

8 Syncope 87 

Mark D. Carlson 

9 Dizziness and Vertigo 96 

Robert B. Daroff 

1 Weakness and Paralysis 1 02 

Michael J. Aminoff 

1 1 Gait and Balance Disorders 109 

Lewis Sudarsky 



12 Numbness, Tingling, and Sensory Loss 116 

Michael J. Aminoff, Arthur K. Asbury 

13 Confusion and Delirium 122 

Scott Andrew Josephson, Bruce L. Miller 

14 Coma 130 

Allan H. Ropper 

15 Aphasia, Memory Loss, and Other Focal 

Cerebral Disorders 140 

M.-Marsel Mesulam 

16 Sleep Disorders 155 

Charles A. Czeislerjohn W.Winkelman, 

Gary S. Richardson 

1 7 Disorders of Vision 170 

Jonathan C Horton 

18 Disorders of Smell, Taste, and Hearing 193 

Anil K. Lalwani 

SECTION III 

DISEASES OF THE CENTRAL 

NERVOUS SYSTEM 

19 Mechanisms of Neurologic Diseases 210 

Stephen L. Hauser, M. Flint Beal 

20 Seizures and Epilepsy 222 

Daniel H. Lowenstein 

21 Cerebrovascular Diseases 246 

Wade S. Smith, Joey D. English, 

S. Claiborne Johnston 

22 Neurologic Critical Care, Including 
Hypoxic-Ischemic Encephalopathy and 
Subarachnoid Hemorrhage 282 

J. Claude Hemphill, III, Wade S. Smith 

23 Alzheimer's Disease and Other 

Dementias 298 

Thomas D. Bird, Bruce L. Miller 



VII 



Contents 



24 Parkinson's Disease and Other Extrapyramidal 

Movement Disorders 320 

Mahlon R. DeLong, Jorge L.Juncos 

25 Hyperkinetic Movement Disorders 337 

C. Warren Olanow 

26 Ataxic Disorders 346 

Roger N. Rosenberg 

27 Amyotrophic Lateral Sclerosis and Other 

Motor Neuron Diseases 358 

Robert H. Brown, Jr. 

28 Disorders of the Autonomic 

Nervous System 366 

Phillip A. Low, John W. Engstrom 

29 Trigeminal Neuralgia, Bell's Palsy, and 

Other Cranial Nerve Disorders 377 

M. Flint Beal, Stephen L. Hauser 

30 Diseases of the Spinal Cord 385 

Stephen L. Hauser, Allan H. Ropper 

31 Concussion and Other Head Injuries 400 

Allan H. Ropper 

32 Primary and Metastatic Tumors of the 

Nervous System 408 

Stephen M. Sagar, Mark A. Israel 

33 Neurologic Disorders of the Pituitary 

and Hypothalamus 423 

Shlomo Melmed,J. Larry Jameson, 
Gary L. Robertson 

34 Multiple Sclerosis and Other 

Demyelinating Diseases 435 

Stephen L. Hauser, Douglas S. Goodin 

35 Meningitis, Encephalitis, Brain Abscess, 

and Empyema 451 

Karen L. Roos, Kenneth L. Tyler 

36 Chronic and Recurrent Meningitis 484 

Walter J. Koroshetz, Morton N. Swartz 

37 HIV Neurology 493 

Anthony S. Fauci, H. Clifford Lane 

38 Prion Diseases 507 

Stanley B. Prusiner, Bruce L. Miller 



39 Paraneoplastic Neurologic Syndromes 516 

Josep Dalmau, Myrna R. Rosenfeld 

40 Peripheral Neuropathy 525 

Vinay Chaudhry 

41 Guillain-Barre Syndrome and Other 

Immune-Mediated Neuropathies 550 

Stephen L. Hauser, Arthur KAsbury 

42 Myasthenia Gravis and Other Diseases 

of the Neuromuscular Junction 559 

Daniel B. Drachman 

43 Muscular Dystrophies and Other 

Muscle Diseases 568 

Robert H. Brown, Jr., Anthony A. Amato, 
Jerry R. Mendell 

44 Polymyositis, Dermatomyositis, and 

Inclusion Body Myositis 597 

Marinos C. Dalakas 

45 Special Issues in Inpatient Neurologic 
Consultation 609 

Scott Andrew Josephson, Martin A. Samuels 

46 Atlas of Neuroimaging 617 

Andre Furtado, William P. Dillon 

SECTION IV 
CHRONIC FATIGUE SYNDROME 

47 Chronic Fatigue Syndrome 650 

Stephen E. Straus 

SECTION V 
PSYCHIATRIC DISORDERS 

48 Biology of Psychiatric Disorders 654 

Steven E. Hyman, Eric Kandel 

49 Mental Disorders 662 

Victor I. Reus 

SECTION VI 

ALCOHOLISM AND DRUG 

DEPENDENCY 

50 Alcohol and Alcoholism 686 

Marc A. Schuckit 



Contents 



51 Opioid Drug Abuse and Dependence . 
Marc A. Schuckit 

52 Cocaine and Other Commonly 

Abused Drugs 

Jack H. Mendelson, Nancy K. Mello 



696 



702 



Review and Self-Assessment 709 

Charles Wiener, Gerald Bloomfield, 

Cynthia D. Brown, Joshua Schiffer,Adam Spivak 

Index 739 



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CONTRIBUTORS 



Numbers in brackets refer to the chapter(s) written or co-written by the contributor. 



ANTHONY A. AMATO, MD 

Associate Professor of Neurology, Harvard Medical School; Chief, 
Division of Neuromuscular Diseases, Department of Neurology, 
Brigham and Women's Hospital, Boston [43] 

MICHAEL J. AMINOFF, MD, DSc 

Professor of Neurology, School of Medicine, 
University of California, San Francisco [3, 10, 12] 

ARTHUR K. ASBURY, MD 

Van Meter Professor of Neurology Emeritus, University of 
Pennsylvania School of Medicine, Philadelphia [12, 41] 

M. FLINT BEAL, MD 

Anne Parrish Titzel Professor and Chair, Department of Neurology 
and Neuroscience, Weill Medical College of Cornell University; 
Neurologist-in-Chief, New York Presbyterian Hospital, 
New York [19, 29] 

THOMAS D. BIRD, MD 

Professor, Neurology and Medicine, University of Washington; 
Research Neurologist, Geriatric Research Education and Clinical 
Center, VA Puget Sound Health Care System, Seattle [23] 

GERALD BLOOMFIELD, MD, MPH 

Department of Internal Medicine, The Johns Hopkins University 
School of Medicine, Baltimore [Review and Self- Assessment] 

CYNTHIA D. BROWN, MD 

Department of Internal Medicine, The Johns Hopkins University 
School of Medicine, Baltimore [Review and Self- Assessment] 

ROBERT H. BROWN, JR., MD, DPhil 

Neurologist, Massachusetts General Hospital; Professor of Neurology, 
Harvard Medical School, Boston [27, 43] 

MARK D. CARLSON, MD, MA 

Chief Medical Officer and Senior Vice President, Clinical Affairs, St. 
Jude Medical, Sylmar; Adjunct Professor of Medicine, Case Western 
Reserve University, Cleveland [8] 

VINAY CHAUDHRY, MD 

Professor and Vice Chair, The Johns Hopkins University School of 
Medicine; Co-Director, EMG Laboratory, Johns Hopkins Hospital, 
Baltimore [40] 

CHARLES A. CZEISLER, MD, PhD 

Baldino Professor of Sleep Medicine, and Director, Division of Sleep 
Medicine, Harvard Medical School; Chief, Division of Sleep 
Medicine, Department of Medicine, Brigham and Women's Hospital, 
Boston [16] 

MARINOS C. DALAKAS, MD 

Professor of Neurology; Chief, Neuromuscular Diseases Section, 
NINDS, National Institute of Health, Bethesda [44] 

JOSEP DALMAU, MD, PhD 

Professor of Neurology, Division Neuro-Oncology, Department of 
Neurology, Philadelphia [39] 



ROBERT B. DAROFF, MD 

Gilbert W Humphrey Professor of Neurology and Interim Chair, 
Department of Neurology, Case Western Reserve University 
School of Medicine and University Hospitals Case Medical Center, 
Cleveland [9] 

MAHLON R. DELONG, MD 

Timmie Professor of Neurology, Emory University School of 
Medicine, Atlanta [24] 

WILLIAM P. DILLON, MD 

Professor of Radiology, Neurology, and Neurosurgery; Vice-Chair, 
Department of Radiology; Chief, Neuroradiology, University of 
California, San Francisco [2, 46] 

DANIEL B. DRACHMAN, MD 

Professor of Neurology & Neuroscience; WW Smith Charitable 
Trust Professor of Neuroimmunology, The Johns Hopkins University 
School of Medicine, Baltimore [42] 

JOEY D. ENGLISH, MD, PhD 

Assistant Professor of Neurology, University of California, San 
Francisco [21] 

JOHN W. ENGSTROM, MD 

Professor of Neurology; Clinical Chief of Service; Neurology 
Residency Program Director, University of California, 
San Francisco [7, 28] 

ANTHONY S. FAUCI, MD, DSc (Hon), DM&S (Hon), DHL 
(Hon), DPS (Hon), DLM (Hon), DMS (Hon) 

Chief, Laboratory of Immunoregulation; Director, National Institute 
of Allergy and Infectious Diseases, National Institutes of Health, 
Bethesda [37] 

HOWARD L. FIELDS, MD, PhD 

Professor of Neurology; Director, Wheeler Center for Neurobiology 
of Addiction, University of California, San Francisco [5] 

ANDRE FURTADO, MD 

Associate Specialist at the Department of Radiology, Neuroradiology 
Section, University of California, San Francisco [46] 

PETER J. GOADSBY, MD, PhD, DSc 

Professor of Clinical Neurology, Institute of Neurology, Queen 
Square London; Professor of Neurology, Department of Neurology, 
University of California, San Francisco [6] 

DOUGLAS S. GOODIN, MD 

Professor of Neurology, University of California, San Francisco [34] 

STEPHEN L. HAUSER, MD 

Robert A. Fishman Distinguished Professor and Chairman, 
Department of Neurology, University of California, San Francisco 
[1,4,19,29,30,34,41] 

J. CLAUDE HEMPHILL, III, MD, MAS 

Associate Professor of Clinical Neurology and Neurological Surgery, 
University of California, San Francisco; Director, Neurocritical Care 
Program, San Francisco General Hospital, San Francisco [22] 



XI 






Contributors 



JONATHAN C. HORTON, MD, PhD 

William F. Hoyt Professor of Neuro-Ophfhalmology; Professor of 
Ophthalmology, Neurology, and Physiology, University of California, 
San Francisco [17J 

STEVEN E. HYMAN, MD 

Provost, Harvard University; Professor of Neurobiology, Harvard 
Medical School, Boston [48] 

MARK A. ISRAEL, MD 

Professor of Pediatrics and Genetics, Dartmouth Medical School; 
Director, Norris Cotton Cancer Center, Dartmouth-Hitchcock 
Medical Center, Lebanon [32] 

J. LARRY JAMESON, MD, PhD 

Professor of Medicine;Vice President for Medical Affairs and Lewis 
Landsberg Dean, Northwestern University Feinberg School of 
Medicine, Chicago [33] 

S. CLAIBORNE JOHNSTON, MD, PhD 

Professor, Neurology; Professor, Epidemiology and Biostatistics; 
Director, University of California, San Francisco Stroke Service, 
San Francisco [21] 

SCOTT ANDREW JOSEPHSON, MD 

Assistant Clinical Professor of Neurology, University of California, 
San Francisco [13, 45J 

JORGE L. JUNCOS, MD 

Associate Professor of Neurology, Emory University School of 
Medicine; Director of Neurology, Wesley Woods Hospital, 
Adanta [24] 

ERIC KANDEL, MD 

University Professor; Fred Kavli Professor and Director, Kavli 
Institute for Brain Sciences; Senior Investigator, Howard Hughes 
Medical Institute, Columbia University, New York [48] 

WALTER J. KOROSHETZ, MD 

Deputy Director, National Institute of Neurological Disorders and 
Stroke, National Institutes of Health, Bethesda [36] 

ANIL K. LALWANI, MD 

Mendik Foundation Professor and Chairman, Department of 
Otolaryngology; Professor, Department of Pediatrics; Professor, 
Department of Physiology and Neuroscience, New York University 
School of Medicine, New York [18] 

H. CLIFFORD LANE, MD 

Clinical Director; Director, Division of Clinical Research; Deputy 
Director, Clinical Research and Special Projects; Chief, Clinical and 
Molecular Retrovirology Section, Laboratory of Immunoregulation, 
National Institute of Allergy and Infectious Diseases, National 
Institutes of Health, Bethesda [37] 

PHILLIP A. LOW, MD 

Robert D and Patricia E Kern Professor of Neurology, 
Mayo Clinic College of Medicine, Rochester [28] 

DANIEL H. LOWENSTEIN, MD 

Professor of Neurology; Director, University of California, San 
Francisco Epilepsy Center; Associate Dean for Clinical/Translational 
Research, San Francisco [1 , 20] 

JOSEPH B. MARTIN, MD, PhD, MA (Hon) 

Dean Emeritus of the Faculty of Medicine, Edward R. and 

Anne G. Lefler Professor of Neurobiology, Harvard Medical School, 

Boston [1,5] 



NANCY K. MELLO, PhD 

Professor of Psychology (Neuroscience), Harvard Medical School, 
Boston [52] 

SHLOMO MELMED, MD 

Senior Vice President, Academic Affairs; Associate Dean, Cedars Sinai 
Medical Center, David Geffen School of Medicine at UCLA, 
Los Angeles [33] 

JERRY R. MENDELL, MD 

Professor of Pediatrics, Neurology and Pathology, The Ohio State 
University; Director, Center for Gene Therapy, The Research 
Institute at Nationwide Children's Hospital, Columbus [43] 

JACK H. MENDELSON,* MD 

Professor of Psychiatry (Neuroscience) , Harvard Medical School, 
Belmont [52] 

M.-MARSEL MESULAM, MD 

Director, Cognitive Neurology and Alzheimer's Disease Center; 
Dunbar Professor of Neurology and Psychiatry, Northwestern 
University Feinberg School of Medicine, Chicago [15] 

BRUCE L. MILLER, MD 

AW and Mary Margaret Clausen Distinguished Professor of 
Neurology, University of California, San Francisco School of 
Medicine, San Francisco [13, 23, 38] 

C.WARREN OLANOW, MD 

Henry P. and Georgette Goldschmidt Professor and Chairman of the 
Department of Neurology, Professor of Neuroscience, The Mount 
Sinai School of Medicine, New York [25] 

STANLEY B. PRUSINER, MD 

Director, Institute for Neurodegenerative Diseases; Professor, 
Department of Neurology; Professor, Department of Biochemistry 
and Biophysics, University of California, San Francisco [38] 

NEIL H. RASKIN, MD 

Professor of Neurology, University of California, San Francisco [6] 

VICTOR I. REUS, MD 

Professor, Department of Psychiatry, University of California, San 
Francisco School of Medicine; Attending Physician, Langley Porter 
Hospital and Clinics, San Francisco [49] 

GARY S. RICHARDSON, MD 

Assistant Professor of Psychiatry, Case Western Reserve University, 
Cleveland; Senior Research Scientist, Sleep Disorders and Research 
Center, Henry Ford Hospital, Detroit [16] 

ELIZABETH ROBBINS, MD 

Associate Clinical Professor, University of California, 
San Francisco [4] 

GARY L. ROBERTSON, MD 

Emeritus Professor of Medicine, Northwestern University Feinberg 
School of Medicine, Chicago [33] 

KAREN L. ROOS, MD 

John and Nancy Nelson Professor of Neurology, Indiana University 
School of Medicine, Indianapolis [35] 

ALLAN H. ROPPER, MD 

Executive Vice-Chair, Department of Neurology, Brigham and 
Women's Hospital, Harvard Medical School, Boston [14, 30, 31] 



^Deceased. 



Contributors 



ROGER N. ROSENBERG, MD 

Zale Distinguished Chair and Professor of Neurology, Department of 
Neurology, University ofTexas Southwestern Medical Center, 
Dallas [26] 

MYRNA R. ROSENFELD, MD, PhD 

Associate Professor of Neurology, Division Neuro-Oncology, 
Department of Neurology, University of Pennsylvania, 
Philadelphia [39] 

STEPHEN M. SAGAR, MD 

Professor of Neurology, Case Western Reserve School of Medicine; 
Director of Neuro-Oncology, Ireland Cancer Center, University 
Hospitals of Cleveland, Cleveland [32] 

MARTIN A. SAMUELS, MD, DSc (Hon) 

Chairman, Department of Neurology, Brigham and Women's 
Hospital; Professor of Neurology, Harvard Medical Center, 
Boston [45] 

JOSHUA SCHIFFER, MD 

Department of Internal Medicine, The Johns Hopkins University 
School of Medicine, Baltimore [Review and Self-Assessment] 

MARC A. SCHUCKIT, MD 

Distinguished Professor of Psychiatry, School of Medicine, University 
of California, San Diego; Director, Alcohol Research Center, VA San 
Diego Healthcare System, San Diego [50, 51] 

WADE S. SMITH, MD, PhD 

Professor of Neurology, Daryl R. Cress Endowed Chair of 
Neurocritical Care and Stroke; Director, University of California, 
San Francisco Neurovascular Service, San Francisco [21, 22] 

ADAM SPIVAK, MD 

Department of Internal Medicine, The Johns Hopkins University 
School of Medicine, Baltimore [Review and Self- Assessment] 



STEPHEN E. STRAUS,* MD 

Senior Investigator, Laboratory of Clinical Investigation, National 
Institute of Allergy and Infectious Diseases; Director, National 
Center for Complementary and Alternative Medicine, National 
Institutes of Health, Bethesda [47] 

LEWIS SUDARSKY, MD 

Associate Professor of Neurology, Harvard Medical School; 
Director of Movement Disorders, Brigham and Women's Hospital, 
Boston [11] 

MORTON N. SWARTZ, MD 

Professor of Medicine, Harvard Medical School; Chief, Jackson Firm 
Medical Service and Infectious Disease Unit, Massachusetts General 
Hospital, Boston [36] 

KENNETH L.TYLER, MD 

Reuler-Lewin Family Professor of Neurology and Professor of 
Medicine and Microbiology, University of Colorado Health Sciences 
Center; Chief, Neurology Service, Denver Veterans Affairs Medical 
Center, Denver [35] 

CHARLES WIENER, MD 

Professor of Medicine and Physiology;Vice Chair, Department of 
Medicine; Director, Osier Medical Training Program, The Johns 
Hopkins University School of Medicine, Baltimore 
[Review and Self-Assessment] 

JOHN W. WINKELMAN, MD, PhD 

Assistant Professor of Psychiatry, Harvard Medical School; Medical 
Director, Sleep Health Center, Brigham and Women's Hospital, 
Boston [16] 



^Deceased. 



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PREFACE 



The first edition of Harrison's Neurology in Clinical Medicine 
was an unqualified success. Readers responded enthusiasti- 
cally to the convenient, attractive, expanded, and updated 
stand-alone volume, which was based upon the neurology 
and psychiatry sections from Harrison's Principles of Internal 
Medicine. Our original goal was to provide, in an easy-to- 
use format, full coverage of the most authoritative infor- 
mation available anywhere of clinically important topics in 
neurology and psychiatry, while retaining the focus on 
pathophysiology and therapy that has always been charac- 
teristic of Harrison's. 

This new edition of Harrison's Neurology in Clinical 
Medicine has been extensively rewritten to highlight 
recent advances in the understanding, diagnosis, treat- 
ment and prevention of neurologic and psychiatric 
diseases. New chapters discuss the pathogenesis and 
treatment of headache, the clinical approach to imbal- 
ance, and the causes of confusion and delirium. Notable 
also are new chapters on essential tremor and move- 
ment disorders, peripheral neuropathy, and on neuro- 
logic problems in hospitalized patients. Many illustrative 
neuroimaging figures appear throughout the section, 
and a new atlas of neuroimaging findings has been 
added. Extensively updated coverage of the dementias, 
Parkinson's disease, and related neurodegenerative dis- 
orders highlight new findings from genetics, molecular 
imaging, cell biology, and clinical research that have 
transformed understanding of these common problems. 
Another new chapter, authored by Steve Hyman and 
Eric Kandel, reviews progress in deciphering the patho- 
genesis of common psychiatric disorders and discusses 
the remaining challenges to development of more effec- 
tive treatments. 

For many physicians, neurologic diseases represent 
particularly challenging problems. Acquisition of the req- 
uisite clinical skills is often viewed as time-consuming, 
difficult to master, and requiring a working knowl- 
edge of obscure anatomic facts and laundry lists of 
diagnostic possibilities. The patients themselves may 
be difficult, as neurologic disorders often alter an 
individual's capacity to recount the history of an ill- 
ness or to even recognize that something is wrong. 
An additional obstacle is the development of inde- 
pendent neurology services, departments, and training 
programs at many medical centers, reducing the ex- 
posure of trainees in internal medicine to neurologic 



problems. All of these forces, acting within the fast- 
paced environment of modern medical practice, can 
lead to an overreliance on unfocused neuroimaging 
tests, suboptimal patient care, and unfortunate out- 
comes. Because neurologists represent less than 1% of 
all physicians, the vast majority of neurologic care 
must be delivered by nonspecialists who are often 
generalists and usually internists. 

The old adage that neurologists "know everything 
but do nothing" has been rendered obsolete by advances 
in molecular medicine, imaging, bioengineering, and 
clinical research. Examples of new therapies include: 
thrombolytic therapy for acute ischemic stroke; endovas- 
cular recanalization for cerebrovascular disorders; inten- 
sive monitoring of brain pressure and cerebral blood 
flow for brain injury; effective therapies for immune- 
mediated neurologic disorders such as multiple sclerosis, 
immune neuropathies, myasthenia gravis, and myositis; 
new designer drugs for migraine; the first generation of 
rational therapies for neurodegenerative diseases; neural 
stimulators for Parkinson's disease; drugs for narcolepsy 
and other sleep disorders; and control of epilepsy by 
surgical resection of small seizure foci precisely local- 
ized by functional imaging and electrophysiology. The 
pipeline continues to grow, stimulated by a quickening 
tempo of discoveries generating opportunities for 
rational design of new diagnostics, interventions, and 
drugs. 

The founding editors of Harrison's Principles of Inter- 
nal Medicine acknowledged the importance of neurol- 
ogy but were uncertain as to its proper role in a text- 
book of internal medicine. An initial plan to exclude 
neurology from the first edition (1950) was reversed at 
the eleventh hour, and a neurology section was hastily 
prepared by Houston Merritt. By the second edition, 
the section was considerably enlarged by Raymond D. 
Adams, whose influence on the textbook was profound. 
The third neurology editor, Joseph B. Martin, brilliantly 
led the book during the 1980s and 1990s as neurology 
was transformed from a largely descriptive discipline to 
one of the most dynamic and rapidly evolving areas of 
medicine. With these changes, the growth of neurology 
coverage in Harrison's became so pronounced that 
Harrison suggested the book be retitled, "The Details of 
Neurology and Some Principles of Internal Medicine." 
His humorous comment, now legendary, underscores the 



XV 






Preface 



depth of coverage of neurologic medicine in Harrison's be- 
fitting its critical role in the practice of internal medicine. 

The Editors are indebted to our authors, a group of 
internationally recognized authorities who have magnif- 
icently distilled a daunting body of information into the 
essential principles required to understand and manage 
commonly encountered neurological problems. We are 
also grateful to Dr. Andrew Scott Josephson who over- 
saw the updating process for the second edition of 
Harrison's Neurology in Clinical Medicine. Thanks also to 
Dr. Elizabeth Robbins, who has served for more than a 
decade as managing editor of the neurology section of 
Harrison's; she has overseen the complex logistics re- 
quired to produce a multiauthored textbook, and has 
promoted exceptional standards for clarity, language and 
style. Finally, we wish to acknowledge and express our 
great appreciation to our colleagues at McGraw-Hill. 
This new volume was championed by James Shanahan 
and impeccably managed by Kim Davis. 

We live in an electronic, wireless age. Information is 
downloaded rather than pulled from the shelf. Some 
have questioned the value of traditional books in this 
new era. We believe that as the volume of information, 
and the ways to access this information, continues to 
grow, the need to grasp the essential concepts of medical 
practice becomes even more challenging. One of our 
young colleagues recently remarked that he uses the 
Internet to find facts, but that he reads Harrison's to learn 
medicine. Our aim has always been to provide 
the reader with an integrated, organic summary of the 
science and the practice of medicine rather than a mere 
compendium of chapters, and we are delighted and 
humbled by the continuing and quite remarkable growth 
in popularity of Harrison's at a time when many "classics" 
in medicine seem less relevant than in years past. 

It is our sincere hope that you will enjoy using Harrison's 
Neurology in Clinical Medicine, Second Edition as an authorita- 
tive source for the most up-to-date information in clinical 
neurology. 



NOTE TO READERS ON ELECTRONIC 
ACCESS TO THE FAMILY OF 
HARRISON'S PUBLICATIONS 
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Review and self-assessment questions and answers -were taken from Wiener C, 
Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J 
(editors) Bloomfield G, Brown CD, Schiffer J, Spivak A (contributing editors). 
Harrison's Principles of Internal Medicine Self-Assessment and Board Review, 17 th ed. 
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Daniel H. Lowenstein ■ Joseph B. Martin ■ Stephen L Hauser 



The Neurologic Method 2 

The Neurologic History 3 

The Neurologic Examination 4 

Neurologic Diagnosis 9 

Further Readings 10 



Neurologic diseases are common and costly. According 
to one estimate, 180 million Americans suffer from a 
nervous system disorder, resulting in an annual cost of 
over $700 billion. The aggregate cost is even greater 
than that for cardiovascular disease (Table 1-1). Glob- 
ally, these disorders are responsible for 28% of all years 
lived with a disability. Most patients with neurologic 
symptoms seek care from internists and other generalists 
rather than from neurologists. Because therapies now 
exist for many neurologic disorders, a skillful approach 
to diagnosis is essential. Errors commonly result from an 
overreliance on costly neuroimaging procedures and 
laboratory tests, which, although useful, do not substi- 
tute for an adequate history and examination. The 
proper approach to the patient with a neurologic illness 
begins with the patient and focuses the clinical problem 
first in anatomic and then in pathophysiologic terms; 
only then should a specific diagnosis be entertained. 
This method ensures that technology is judiciously 
applied, a correct diagnosis is established in an efficient 
manner, and treatment is promptly initiated. 

THE NEUROLOGIC METHOD 

Locate the Lesion(s) 

The first priority is to identify the region of the nervous 
system that is likely to be responsible for the symptoms. 
Can the disorder be mapped to one specific location, is 
it multifocal, or is a diffuse process present? Are the 



symptoms restricted to the nervous system, or do they 
arise in the context of a systemic illness? Is the problem 
in the central nervous system (CNS), the peripheral ner- 
vous system (PNS), or both? If in the CNS, is the cere- 
bral cortex, basal ganglia, brainstem, cerebellum, or 
spinal cord responsible? Are the pain-sensitive meninges 
involved? If in the PNS, could the disorder be located in 
peripheral nerves and, if so, are motor or sensory nerves 
primarily affected, or is a lesion in the neuromuscular 
junction or muscle more likely? 

The first clues to defining the anatomic area of 
involvement appear in the history, and the examination 
is then directed to confirm or rule out these impressions 
and to clarify uncertainties. A more detailed examina- 
tion of a particular region of the CNS or PNS is often 
indicated. For example, the examination of a patient 
who presents with a history of ascending paresthesias 
and weakness should be directed toward deciding, 
among other things, if the location of the lesion is in the 
spinal cord or peripheral nerves. Focal back pain, a spinal 
cord sensory level, and incontinence suggest a spinal 
cord origin, whereas a stocking-glove pattern of sensory 
loss suggests peripheral nerve disease; areflexia usually 
indicates peripheral neuropathy but may also be present 
with spinal shock in acute spinal cord disorders. 

Deciding "where the lesion is" accomplishes the task 
of limiting the possible etiologies to a manageable, finite 
number. In addition, this strategy safeguards against 
making serious errors. Symptoms of recurrent vertigo, 
diplopia, and nystagmus should not trigger "multiple 



TABLE 1-1 



PREVALENCE OF NEUROLOGIC AND PSYCHIATRIC 
DISEASES WORLDWIDE 



DISORDER 


PATIENTS, MILLIONS 


Nutritional disorders and 


352 


neuropathies 




Migraine 


326 


Trauma 


170 


Depression 


154 


Alcoholism 


91 


Cerebrovascular diseases 


61 


Epilepsy 


50 


Schizophrenia 


25 


Dementia 


24 


Neurologic infections 


18 


Drug abuse 


15 



Source: World Health Organization estimates, 2002-2005. 

sclerosis" as an answer (etiology) but "brainstem" or 
"pons" (location); then a diagnosis of brainstem arteri- 
ovenous malformation will not be missed for lack of 
consideration. Similarly, the combination of optic neuri- 
tis and spastic ataxic paraparesis should initially suggest 
optic nerve and spinal cord disease; multiple sclerosis 
(MS), CNS syphilis, and vitamin B 12 deficiency are 
treatable disorders that can produce this syndrome. Once 
the question, "Where is the lesion?" is answered, then 
the question, "What is the lesion?" can be addressed. 

Define the Pathophysiology 

Clues to the pathophysiology of the disease process may 
also be present in the history. Primary neuronal (gray 
matter) disorders may present as early cognitive distur- 
bances, movement disorders, or seizures, whereas -white 
matter involvement produces predominantly "long 
tract" disorders of motor, sensory, visual, and cerebellar 
pathways. Progressive and symmetric symptoms often 
have a metabolic or degenerative origin; in such cases 
lesions are usually not sharply circumscribed. Thus, a 
patient with paraparesis and a clear spinal cord sensory 
level is unlikely to have vitamin B 12 deficiency as the 
explanation. A Lhermitte symptom (electric shock— like 
sensations evoked by neck flexion) is due to ectopic 
impulse generation in white matter pathways and occurs 
with demyelination in the cervical spinal cord; among 
many possible causes, this symptom may indicate MS in 
a young adult or compressive cervical spondylosis in an 
older person. Symptoms that worsen after exposure to 
heat or exercise may indicate conduction block in 
demyelinated axons, as occurs in MS. A patient with 
recurrent episodes of diplopia and dysarthria associated 
with exercise or fatigue may have a disorder of neuro- 
muscular transmission such as myasthenia gravis. Slowly 



advancing visual scotoma with luminous edges, termed 3 
fortification spectra, indicates spreading cortical depression, 
typically with migraine. 

THE NEUROLOGIC HISTORY 

Attention to the description of the symptoms experi- 
enced by the patient and substantiated by family mem- 
bers and others often permits an accurate localization 
and determination of the probable cause of the com- 
plaints, even before the neurologic examination is per- 
formed. The history also helps to bring a focus to the 
neurologic examination that follows. Each complaint 
should be pursued as far as possible to elucidate the 
location of the lesion, the likely underlying pathophysi- 
ology, and potential etiologies. For example, a patient 
complains of weakness of the right arm. What are the 
associated features? Does the patient have difficulty with 
brushing hair or reaching upward (proximal) or button- 
ing buttons or opening a twist-top bottle (distal)? Nega- 
tive associations may also be crucial. A patient with a 
right hemiparesis without a language deficit likely has a 
lesion (internal capsule, brainstem, or spinal cord) differ- 
ent from that of a patient with a right hemiparesis and 
aphasia (left hemisphere). Other pertinent features of the 
history include the following: 

1. Temporal course of the illness. It is important to deter- 
mine the precise time of appearance and rate of 
progression of the symptoms experienced by the 
patient. The rapid onset of a neurologic complaint, 
occurring within seconds or minutes, usually indi- 
cates a vascular event, a seizure, or migraine. The 
onset of sensory symptoms located in one extremity 
that spread over a few seconds to adjacent portions 
of that extremity and then to the other regions of 
the body suggests a seizure. A more gradual onset 
and less well localized symptoms point to the possi- 
bility of a transient ischemic attack (TIA) . A similar 
but slower temporal march of symptoms accompa- 
nied by headache, nausea, or visual disturbance sug- 
gests migraine. The presence of "positive" sensory 
symptoms (e.g., tingling or sensations that are diffi- 
cult to describe) or involuntary motor movements 
suggests a seizure; in contrast, transient loss of func- 
tion (negative symptoms) suggests a TIA. A stutter- 
ing onset where symptoms appear, stabilize, and 
then progress over hours or days also suggests cere- 
brovascular disease; an additional history of transient 
remission or regression indicates that the process is 
more likely due to ischemia rather than hemor- 
rhage. A gradual evolution of symptoms over hours 
or days suggests a toxic, metabolic, infectious, or 
inflammatory process. Progressing symptoms associ- 
ated with the systemic manifestations of fever, stiff 



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neck, and altered level of consciousness imply an 
infectious process. Relapsing and remitting symp- 
toms involving different levels of the nervous system 
suggest MS or other inflammatory processes; these 
disorders can occasionally produce new symptoms 
that are rapidly progressive over hours. Slowly pro- 
gressive symptoms without remissions are character- 
istic of neurodegenerative disorders, chronic infec- 
tions, gradual intoxications, and neoplasms. 

2. Patients' descriptions of the complaint. The same words 
often mean different things to different patients. 
"Dizziness" may imply impending syncope, a sense 
of disequilibrium, or true spinning vertigo. "Numb- 
ness" may mean a complete loss of feeling, a positive 
sensation such as tingling, or paralysis. "Blurred 
vision" may be used to describe unilateral visual 
loss, as in transient monocular blindness, or diplopia. 
The interpretation of the true meaning of the words 
used by patients to describe symptoms becomes 
even more complex when there are differences in 
primary languages and cultures. 

3. Corroboration of the history by others. It is almost always 
helpful to obtain additional information from fam- 
ily, friends, or other observers to corroborate or 
expand the patient's description. Memory loss, apha- 
sia, loss of insight, intoxication, and other factors 
may impair the patient's capacity to communicate 
normally with the examiner or prevent openness 
about factors that have contributed to the illness. 
Episodes of loss of consciousness necessitate that 
details be sought from observers to ascertain pre- 
cisely what has happened during the event. 

4. Family history. Many neurologic disorders have an 
underlying genetic component. The presence of a 
Mendelian disorder, such as Huntington's disease or 
Charcot-Marie-Tooth neuropathy, is often obvious 
if family data are available. More detailed questions 
about family history are often necessary in poly- 
genic disorders such as MS, migraine, and many 
types of epilepsy. It is important to elicit family his- 
tory about all illnesses, in addition to neurologic and 
psychiatric disorders. A familial propensity to hyper- 
tension or heart disease is relevant in a patient who 
presents with a stroke. There are numerous inherited 
neurologic diseases that are associated with multisys- 
tem manifestations that may provide clues to the 
correct diagnosis (e.g., neurofibromatosis, Wilson's 
disease, neuro-ophthalmic syndromes) . 

5. Medical illnesses. Many neurologic diseases occur in the 
context of systemic disorders. Diabetes mellitus, 
hypertension, and abnormalities of blood lipids predis- 
pose to cerebrovascular disease. A solitary mass lesion 
in the brain may be an abscess in a patient with valvu- 
lar heart disease, a primary hemorrhage in a patient 
with a coagulopathy, a lymphoma or toxoplasmosis in 
a patient with AIDS (Chap. 37), or a metastasis in a 



patient with underlying cancer. Patients with malig- 
nancy may also present with a neurologic paraneo- 
plastic syndrome (Chap. 39) or complications from 
chemotherapy or radiotherapy. Marian's syndrome and 
related collagen disorders predispose to dissection of 
the cranial arteries and aneurysmal subarachnoid 
hemorrhage; the latter may also occur with polycystic 
kidney disease. Various neurologic disorders occur 
with dysthyroid states or other endocrinopathies. It is 
especially important to look for the presence of sys- 
temic diseases in patients with peripheral neuropathy. 
Most patients with coma in a hospital setting have a 
metabolic, toxic, or infectious cause. 

6. Drug use and abuse and toxin exposure. It is essential to 
inquire about the history of drug use, both pre- 
scribed and illicit. Aminoglycoside antibiotics may 
exacerbate symptoms of weakness in patients with 
disorders of neuromuscular transmission, such as 
myasthenia gravis, and may cause dizziness sec- 
ondary to ototoxicity. Vincristine and other anti- 
neoplastic drugs can cause peripheral neuropathy, 
and immunosuppressive agents such as cyclosporine 
can produce encephalopathy. Excessive vitamin 
ingestion can lead to disease; for example vitamin A 
and pseudotumor cerebri, or pyridoxine and 
peripheral neuropathy. Many patients are unaware 
that over-the-counter sleeping pills, cold prepara- 
tions, and diet pills are actually drugs. Alcohol, the 
most prevalent neurotoxin, is often not recognized 
as such by patients, and other drugs of abuse such as 
cocaine and heroin can cause a wide range of neu- 
rologic abnormalities. A history of environmental or 
industrial exposure to neurotoxins may provide an 
essential clue; consultation with the patient's co- 
workers or employer may be required. 

7. Formulating an impression of the patient. Use the 
opportunity while taking the history to form an 
impression of the patient. Is the information forth- 
coming, or does it take a circuitous course? Is there 
evidence of anxiety, depression, or hypochondriasis? 
Are there any clues to defects in language, memory, 
insight, or inappropriate behavior? The neurologic 
assessment begins as soon as the patient comes into 
the room and the first introduction is made. 



THE NEUROLOGIC EXAMINATION 

The neurologic examination is challenging and com- 
plex; it has many components and includes a number of 
skills that can be mastered only through repeated use of 
the same techniques on a large number of individuals 
with and without neurologic disease. Mastery of the 
complete neurologic examination is usually important 
only for physicians in neurology and associated specialties. 
However, knowledge of the basics of the examination, 



especially those components that are effective in screen- 
ing for neurologic dysfunction, is essential for all clini- 
cians, especially generalists. 

There is no single, universally accepted sequence of 
the examination that must be followed, but most clini- 
cians begin with assessment of mental status followed by 
the cranial nerves, motor system, sensory system, coordi- 
nation, and gait. Whether the examination is basic or 
comprehensive, it is essential that it be performed in an 
orderly and systematic fashion to avoid errors and seri- 
ous omissions. Thus, the best way to learn and gain 
expertise in the examination is to choose one's own 
approach and practice it frequently and do it in exactly 
the same sequence each time. 

The detailed description of the neurologic examina- 
tion that follows describes the more commonly used 
parts of the examination, with a particular emphasis on 
the components that are considered most helpful for the 
assessment of common neurologic problems. Each sec- 
tion also includes a brief description of the minimal 
examination necessary for adequate screening for abnor- 
malities in a patient who has no symptoms suggesting 
neurologic dysfunction. A screening examination done 
in this way can be completed in 3—5 min. 

Several additional points about the examination are 
worth noting. First, in recording observations, it is 
important to describe what is found rather than to apply 
a poorly defined medical term (e.g., "patient groans to 
sternal rub" rather than "obtunded"). Second, subtle 
CNS abnormalities are best detected by carefully com- 
paring a patient's performance on tasks that require 
simultaneous activation of both cerebral hemispheres 
(e.g., eliciting a pronator drift of an outstretched arm 
with the eyes closed; extinction on one side of bilaterally 
applied light touch, also with eyes closed; or decreased 
arm swing or a slight asymmetry when walking) . Third, 
if the patient's complaint is brought on by some activity, 
reproduce the activity in the office. If the complaint is 
of dizziness when the head is turned in one direction, 
have the patient do this and also look for associated signs 
on examination (e.g., nystagmus or dysmetria). If pain 
occurs after walking two blocks, have the patient leave 
the office and walk this distance and immediately 
return, and repeat the relevant parts of the examination. 
Finally, the use of tests that are individually tailored to 
the patient's problem can be of value in assessing 
changes over time. Tests of walking a 7.5-m (25-ft) dis- 
tance (normal, 5—6 s; note assistance, if any), repetitive 
finger or toe tapping (normal, 20—25 taps in 5 s), or hand- 
writing are examples. 

Mental Status Examination 

• The bare minimum: During the interview, look for difficul- 
ties with communication and determine whether the patient has 
recall and insight into recent and past events. 



The mental status examination is underway as soon as 
the physician begins observing and talking with the 
patient. If the history raises any concern for abnormali- 
ties of higher cortical function or if cognitive problems 
are observed during the interview, then detailed testing 
of the mental status is indicated. The patient's ability to 
understand the language used for the examination, cul- 
tural background, educational experience, sensory or 
motor problems, or comorbid conditions need to be 
factored into the applicability of the tests and interpreta- 
tion of results. 

The Folstein mini-mental status examination (MMSE) 
(Table 23-5) is a standardized screening examination of 
cognitive function that is extremely easy to administer 
and takes <10 min to complete. Using age-adjusted val- 
ues for defining normal performance, the test is ~85% 
sensitive and 85% specific for making the diagnosis of 
dementia that is moderate or severe, especially in edu- 
cated patients. When there is sufficient time available, 
the MMSE is one of the best methods for documenting 
the current mental status of the patient, and this is espe- 
cially useful as a baseline assessment to which future 
scores of the MMSE can be compared. 

Individual elements of the mental status examination 
can be subdivided into level of consciousness, orienta- 
tion, speech and language, memory, fund of information, 
insight and judgment, abstract thought, and calculations. 

Level of consciousness is the patient's relative state of 
awareness of the self and the environment, and ranges 
from fully awake to comatose. When the patient is not 
fully awake, the examiner should describe the responses 
to the minimum stimulus necessary to elicit a reaction, 
ranging from verbal commands to a brief, painful stimu- 
lus such as a squeeze of the trapezius muscle. Responses 
that are directed toward the stimulus and signify some 
degree of intact cerebral function (e.g., opening the eyes 
and looking at the examiner or reaching to push away a 
painful stimulus) must be distinguished from reflex 
responses of a spinal origin (e.g., triple flexion response — 
flexion at the ankle, knee, and hip in response to a 
painful stimulus to the foot) . 

Orientation is tested by asking the patient to state his 
or her name, location, and time (day of the week and 
date); time is usually the first to be affected in a variety 
of conditions. 

Speech is assessed by observing articulation, rate, 
rhythm, and prosody (i.e., the changes in pitch and 
accentuation of syllable and words). 

Language is assessed by observing the content of the 
patient's verbal and written output, response to spoken 
commands, and ability to read. A typical testing 
sequence is to ask the patient to name successively more 
detailed components of clothing, a watch or a pen; 
repeat the phrase "No ifs, ands, or buts"; follow a three- 
step, verbal command; write a sentence; and read and 
respond to a written command. 



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Memory should be analyzed according to three main 
time scales: (1) immediate memory can be tested by say- 
ing a list of three items and having the patient repeat the 
list immediately, (2) short-term memory is assessed by 
asking the patient to recall the same three items 5 and 
15 min later, and (3) long-term memory is evaluated by 
determining how well the patient is able to provide a 
coherent chronologic history of his or her illness or per- 
sonal events. 

Fund of information is assessed by asking questions 
about major historic or current events, with special 
attention to educational level and life experiences. 

Abnormalities of insight and judgment are usually 
detected during the patient interview; a more detailed 
assessment can be elicited by asking the patient to 
describe how he or she would respond to situations 
having a variety of potential outcomes (e.g., "What 
would you do if you found a wallet on the sidewalk?"). 

Abstract thought can be tested by asking the patient to 
describe similarities between various objects or concepts 
(e.g., apple and orange, desk and chair, poetry and sculp- 
ture) or to list items having the same attributes (e.g., a 
list of four -legged animals). 

Calculation ability is assessed by having the patient 
carry out a computation that is appropriate to the 
patient's age and education (e.g., serial subtraction of 7 
from 100 or 3 from 20; or word problems involving 
simple arithmetic). 



Cranial Nerve Examination 

• The bare minimum: Check the fundi, visual fields, pupil size 
and reactivity, extraocular movements, and facial movements. 

The cranial nerves (CN) are best examined in 
numerical order, except for grouping together CN III, 
IV, and VI because of their similar function. 

^M CN I (Olfactory) 

Testing is usually omitted unless there is suspicion for 
inferior frontal lobe disease (e.g., meningioma). With 
eyes closed, ask the patient to sniff a mild stimulus such 
as toothpaste or coffee and identify the odorant. 

^m CN II (Optic) 

Check visual acuity (with eyeglasses or contact lens cor- 
rection) using a Snellen chart or similar tool. Test the 
visual fields by confrontation, i.e., by comparing the 
patient's visual fields to your own. As a screening test, it 
is usually sufficient to examine the visual fields of both 
eyes simultaneously; individual eye fields should be 
tested if there is any reason to suspect a problem of 
vision by the history or other elements of the examina- 
tion, or if the screening test reveals an abnormality. Face 
the patient at a distance of approximately 0.6—1.0 m 
(2—3 ft) and place your hands at the periphery of your 



visual fields in the plane that is equidistant between you 
and the patient. Instruct the patient to look directly at 
the center of your face and to indicate when and where 
he or she sees one of your fingers moving. Beginning 
with the two inferior quadrants and then the two supe- 
rior quadrants, move your index finger of the right 
hand, left hand, or both hands simultaneously and 
observe whether the patient detects the movements. A 
single small-amplitude movement of the finger is suffi- 
cient for a normal response. Focal perimetry and tangent 
screen examinations should be used to map out visual 
field defects fully or to search for subtle abnormalities. 
Optic fundi should be examined with an ophthalmo- 
scope, and the color, size, and degree of swelling or ele- 
vation of the optic disc noted, as well as the color and 
texture of the retina. The retinal vessels should be 
checked for size, regularity, arterial-venous nicking at 
crossing points, hemorrhage, exudates, etc. 

^H CN III, IV, VI (Oculomotor, Trochlear, Abducens) 

Describe the size and shape of pupils and reaction to 
light and accommodation (i.e., as the eyes converge 
while following your finger as it moves toward the 
bridge of the nose). To check extraocular movements, 
ask the patient to keep his or her head still while track- 
ing the movement of the tip of your finger. Move the 
target slowly in the horizontal and vertical planes; 
observe any paresis, nystagmus, or abnormalities of 
smooth pursuit (saccades, oculomotor ataxia, etc.). If 
necessary, the relative position of the two eyes, both in 
primary and multidirectional gaze, can be assessed by 
comparing the reflections of a bright light off both 
pupils. However, in practice it is typically more useful to 
determine whether the patient describes diplopia in any 
direction of gaze; true diplopia should almost always 
resolve with one eye closed. Horizontal nystagmus is 
best assessed at 45° and not at extreme lateral gaze 
(which is uncomfortable for the patient); the target must 
often be held at the lateral position for at least a few sec- 
onds to detect an abnormality. 

^M CN V (Trigeminal) 

Examine sensation within the three territories of the 
branches of the trigeminal nerve (ophthalmic, maxillary, 
and mandibular) on each side of the face. As with other 
parts of the sensory examination, testing of two sensory 
modalities derived from different anatomic pathways 
(e.g., light touch and temperature) is sufficient for a 
screening examination. Testing of other modalities, the 
corneal reflex, and the motor component of CNV (jaw 
clench — masseter muscle) is indicated when suggested 
by the history. 

^M CN VII (Facial) 

Look for facial asymmetry at rest and with spontaneous 
movements. Test eyebrow elevation, forehead wrinkling, 



eye closure, smiling, and cheek puff. Look in particular 
for differences in the lower versus upper facial muscles; 
weakness of the lower two-thirds of the face with 
preservation of the upper third suggests an upper motor 
neuron lesion, whereas weakness of an entire side sug- 
gests a lower motor neuron lesion. 

^M CN VIM (Vestibulocochlear) 

Check the patient's ability to hear a finger rub or whis- 
pered voice with each ear. Further testing for air versus 
mastoid bone conduction (Rinne) and lateralization of a 
512-Hz tuning fork placed at the center of the forehead 
(Weber) should be done if an abnormality is detected by 
history or examination. Any suspected problem should be 
followed up with formal audiometry. For further discus- 
sion of assessing vestibular nerve function in the setting of 
dizziness or coma, see Chaps. 9 and 14, respectively. 

^H CN IX, X (Glossopharyngeal, Vagus) 

Observe the position and symmetry of the palate and 
uvula at rest and with phonation ("aah").The pharyn- 
geal ("gag") reflex is evaluated by stimulating the poste- 
rior pharyngeal wall on each side with a sterile, blunt 
object (e.g., tongue blade), but the reflex is often absent 
in normal individuals. 

^H CN XI (Spinal Accessory) 

Check shoulder shrug (trapezius muscle) and head rota- 
tion to each side (sternocleidomastoid) against resistance. 

^■CNXII (Hypoglossal) 

Inspect the tongue for atrophy or fasciculations, position 
with protrusion, and strength when extended against the 
inner surface of the cheeks on each side. 

Motor Examination 

• Tlie bare minimum: Look for muscle atrophy and check extrem- 
ity tone. Assess upper extremity strength by checking for pronator 
drift and strength of wrist or finger extensors. Tap the biceps, patel- 
lar, and Achilles reflexes. Test for lower extremity strength by having 
the patient walk normally and on heels and toes. 

The motor examination includes observations of 
muscle appearance, tone, strength, and reflexes. Although 
gait is in part a test of motor function, it is usually evalu- 
ated separately at the end of the examination. 

^H Appearance 

Inspect and palpate muscle groups under good light and 
with the patient in a comfortable and symmetric posi- 
tion. Check for muscle fasciculations, tenderness, and 
atrophy or hypertrophy. Involuntary movements may be 
present at rest (e.g., tics, myoclonus, choreoathetosis), 
during maintained posture (pill-rolling tremor of Parkin- 
son's disease), or with voluntary movements (intention 
tremor of cerebellar disease or familial tremor). 



^■Tone 

Muscle tone is tested by measuring the resistance to pas- 
sive movement of a relaxed limb. Patients often have dif- 
ficulty relaxing during this procedure, so it is useful to 
distract the patient to minimize active movements. In 
the upper limbs, tone is assessed by rapid pronation and 
supination of the forearm and flexion and extension at 
the wrist. In the lower limbs, while the patient is supine 
the examiner's hands are placed behind the knees and 
rapidly raised; with normal tone the ankles drag along 
the table surface for a variable distance before rising, 
whereas increased tone results in an immediate lift of 
the heel off the surface. Decreased tone is most com- 
monly due to lower motor neuron or peripheral nerve 
disorders. Increased tone may be evident as spasticity 
(resistance determined by the angle and velocity of 
motion; corticospinal tract disease), rigidity (similar 
resistance in all angles of motion; extrapyramidal dis- 
ease), or paratonia (fluctuating changes in resistance; 
frontal lobe pathways or normal difficulty in relaxing). 
Cogwheel rigidity, in which passive motion elicits jerky 
interruptions in resistance, is seen in parkinsonism. 

^H Strength 

Testing for pronator drift is an extremely useful method 
for screening upper limb -weakness. The patient is asked to 
hold both arms fully extended and parallel to the ground 
with eyes closed. This position should be maintained for 
~10 s; any flexion at the elbow or fingers or pronation of 
the forearm, especially if asymmetric, is a sign of potential 
weakness. Muscle strength is further assessed by having 
the patient exert maximal effort for the particular muscle 
or muscle group being tested. It is important to isolate the 
muscles as much as possible, i.e., hold the limb so that 
only the muscles of interest are active. It is also helpful to 
palpate accessible muscles as they contract. Grading mus- 
cle strength and evaluating the patient's effort is an art 
that takes time and practice. Muscle strength is tradition- 
ally graded using the following scale: 

= no movement 

1 = flicker or trace of contraction but no associated 

movement at a joint 

2 = movement with gravity eliminated 

3 = movement against gravity but not against 

resistance 
4— = movement against a mild degree of resistance 

4 = movement against moderate resistance 
4+ = movement against strong resistance 

5 = full power 

However, in many cases it is more practical to use the 
following terms: 

Paralysis = no movement 
Severe weakness = movement with gravity 
eliminated 



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o 



O 



Moderate weakness = movement against gravity but 

not against mild resistance 
Mild weakness = movement against moderate 

resistance 
Full strength 

Noting the pattern of weakness is as important as 
assessing the magnitude of weakness. Unilateral or bilat- 
eral weakness of the upper limb extensors and lower 
limb flexors ("pyramidal weakness") suggests a lesion of 
the pyramidal tract, bilateral proximal weakness suggests 
myopathy and bilateral distal weakness suggests periph- 
eral neuropathy. 

^H Reflexes 

^H Muscle Stretch Reflexes 

Those that are typically assessed include the biceps (C5, 
C6), brachioradialis (C5, C6), and triceps (C7, C8) 
reflexes in the upper limbs and the patellar or quadri- 
ceps (L3, L4) and Achilles (SI, S2) reflexes in the lower 
limbs. The patient should be relaxed and the muscle 
positioned midway between full contraction and exten- 
sion. Reflexes may be enhanced by asking the patient to 
voluntarily contract other, distant muscle groups (Jen- 
drassik maneuver) . For example, upper limb reflexes may 
be reinforced by voluntary teeth-clenching, and the 
Achilles reflex by hooking the flexed fingers of the two 
hands together and attempting to pull them apart. For 
each reflex tested, the two sides should be tested 
sequentially, and it is important to determine the small- 
est stimulus required to elicit a reflex rather than the 
maximum response. Reflexes are graded according to 
the following scale: 

= absent 

1 = present but diminished 

2 = normoactive 

3 = exaggerated 

4 = clonus 



^H Cutaneous Reflexes 

The plantar reflex is elicited by stroking, with a noxious 
stimulus such as a tongue blade, the lateral surface of the 
sole of the foot beginning near the heel and moving 
across the ball of the foot to the great toe. The normal 
reflex consists of plantar flexion of the toes. With upper 
motor neuron lesions above the SI level of the spinal 
cord, a paradoxical extension of the toe is observed, 
associated with fanning and extension of the other toes 
(termed an extensor plantar response, or Babinski sign). 
Superficial abdominal reflexes are elicited by gently 
stroking the abdominal surface near the umbilicus in a 
diagonal fashion with a sharp object (e.g., the wooden 
end of a cotton-tipped swab) and observing the move- 
ment of the umbilicus. Normally, the umbilicus will pull 



toward the stimulated quadrant. With upper motor neu- 
ron lesions, these reflexes are absent. They are most help- 
ful when there is preservation of the upper (spinal cord 
level T9) but not lower (T12) abdominal reflexes, indi- 
cating a spinal lesion between T9 andT12, or when the 
response is asymmetric. Other useful cutaneous reflexes 
include the cremasteric (ipsilateral elevation of the testi- 
cle following stroking of the medial thigh; mediated by 
LI and L2) and anal (contraction of the anal sphincter 
when the perianal skin is scratched; mediated by S2, S3, 
S4) reflexes. It is particularly important to test for these 
reflexes in any patient with suspected injury to the 
spinal cord or lumbosacral roots. 

^H Primitive Reflexes 

With disease of the frontal lobe pathways, several primi- 
tive reflexes not normally present in the adult may 
appear. The suck response is elicited by lightly touching 
the center of the lips, and the root response the corner 
of the lips, with a tongue blade; the patient will move 
the lips to suck or root in the direction of the stimulus. 
The grasp reflex is elicited by touching the palm 
between the thumb and index finger with the exam- 
iner's fingers; a positive response is a forced grasp of the 
examiner's hand. In many instances stroking the back of 
the hand will lead to its release. The palmomental 
response is contraction of the mentalis muscle (chin) 
ipsilateral to a scratch stimulus diagonally applied to the 
palm. 

Sensory Examination 

• The bare minimum: Ask whether the patient can feel light 
touch and the temperature of a cool object in each distal 
extremity. Check double simultaneous stimulation using light 
touch on the hands. 

Evaluating sensation is usually the most unreliable 
part of the examination, because it is subjective and is 
difficult to quantify. In the compliant and discerning 
patient, the sensory examination can be extremely help- 
ful for the precise localization of a lesion. With patients 
who are uncooperative or lack an understanding of the 
tests, it may be useless. The examination should be 
focused on the suspected lesion. For example, in spinal 
cord, spinal root, or peripheral nerve abnormalities, all 
major sensory modalities should be tested while looking 
for a pattern consistent with a spinal level and der- 
matomal or nerve distribution. In patients with lesions 
at or above the brainstem, screening the primary sensory 
modalities in the distal extremities along with tests of 
"cortical" sensation is usually sufficient. 

The five primary sensory modalities — light touch, 
pain, temperature, vibration, and joint position — are 
tested in each limb. Light touch is assessed by stimulat- 
ing the skin with single, very gentle touches of the 
examiner's finger or a wisp of cotton. Pain is tested 



using a new pin, and temperature is assessed using a 
metal object (e.g., tuning fork) that has been immersed 
in cold and warm water. Vibration is tested using a 128-Hz 
tuning fork applied to the distal phalynx of the great toe 
or index finger just below the nailbed. By placing a fin- 
ger on the opposite side of the joint being tested, the 
examiner compares the patient's threshold of vibration 
perception with his or her own. For joint position test- 
ing, the examiner grasps the digit or limb laterally and 
distal to the joint being assessed; small 1- to 2-mm 
excursions can usually be sensed. The Romberg maneu- 
ver is primarily a test of proprioception. The patient is 
asked to stand with the feet as close together as neces- 
sary to maintain balance while the eyes are open, and 
the eyes are then closed. A loss of balance with the eyes 
closed is an abnormal response. 

"Cortical" sensation is mediated by the parietal lobes 
and represents an integration of the primary sensory 
modalities; testing cortical sensation is only meaningful 
when primary sensation is intact. Double simultaneous 
stimulation is especially useful as a screening test for cor- 
tical function; with the patient's eyes closed, the exam- 
iner lightly touches one or both hands and asks the 
patient to identify the stimuli. With a parietal lobe 
lesion, the patient may be unable to identify the stimulus 
on the contralateral side when both hands are touched. 
Other modalities relying on the parietal cortex include 
the discrimination of two closely placed stimuli as sepa- 
rate (two-point discrimination), identification of an 
object by touch and manipulation alone (stereognosis), 
and the identification of numbers or letters written on 
the skin surface (graphesthesia). 

Coordination Examination 

• The bare minimum: Test rapid alternating movements of the 
hands and the finger-to-nose and heel-knee-shin maneuvers. 

Coordination refers to the orchestration and fluidity 
of movements. Even simple acts require cooperation of 
agonist and antagonist muscles, maintenance of posture, 
and complex servomechanisms to control the rate and 
range of movements. Part of this integration relies on 
normal function of the cerebellar and basal ganglia sys- 
tems. However, coordination also requires intact muscle 
strength and kinesthetic and proprioceptive informa- 
tion. Thus, if the examination has disclosed abnormali- 
ties of the motor or sensory systems, the patient's coor- 
dination should be assessed with these limitations in 
mind. 

Rapid alternating movements in the upper limbs are 
tested separately on each side by having the patient 
make a fist, partially extend the index finger, and then 
tap the index finger on the distal thumb as quickly as 
possible. In the lower limb, the patient rapidly taps the 
foot against the floor or the examiner's hand. Finger-to- 
nose testing is primarily a test of cerebellar function; the 



patient is asked to touch his or her index finger repeti- 
tively to the nose and then to the examiner's out- 
stretched finger, which moves with each repetition. A 
similar test in the lower extremity is to have the patient 
raise the leg and touch the examiner's finger with the 
great toe. Another cerebellar test in the lower limbs is 
the heel-knee-shin maneuver; in the supine position the 
patient is asked to slide the heel of each foot from the 
knee down the shin of the other leg. For all these move- 
ments, the accuracy, speed, and rhythm are noted. 

Gait Examination 

• The bare minimum: Observe the patient while walking nor- 
mally, on the heels and toes, and along a straight line. 

Watching the patient walk is the most important part 
of the neurologic examination. Normal gait requires that 
multiple systems — including strength, sensation, and 
coordination — function in a highly integrated fashion. 
Unexpected abnormalities may be detected that prompt 
the examiner to return, in more detail, to other aspects of 
the examination. The patient should be observed while 
walking and turning normally, walking on the heels, 
walking on the toes, and walking heel-to-toe along a 
straight line. The examination may reveal decreased arm 
swing on one side (corticospinal tract disease), a stooped 
posture and short-stepped gait (parkinsonism), a broad- 
based unstable gait (ataxia), scissoring (spasticity), or a 
high-stepped, slapping gait (posterior column or periph- 
eral nerve disease), or the patient may appear to be stuck 
in place (apraxia with frontal lobe disease). 

NEUROLOGIC DIAGNOSIS 

The clinical data obtained from the history and exami- 
nation are interpreted to arrive at an anatomic localiza- 
tion that best explains the clinical findings (Table 1-2), 
to narrow the list of diagnostic possibilities, and to select 
the laboratory tests most likely to be informative. The 
laboratory assessment may include (1) serum elec- 
trolytes; complete blood count; and renal, hepatic, 
endocrine, and immune studies; (2) cerebrospinal fluid 
examination; (3) focused neuro imaging studies (Chap. 2); 
or (4) electrophysiologic studies (Chap. 3). The anatomic 
localization, mode of onset and course of illness, other 
medical data, and laboratory findings are then integrated 
to establish an etiologic diagnosis. 

The neurologic examination may be normal even in 
patients with a serious neurologic disease, such as 
seizures, chronic meningitis, or a TIA. A comatose 
patient may arrive with no available history, and in such 
cases the approach is as described in Chap. 14. In other 
patients, an inadequate history may be overcome by a 
succession of examinations from which the course of 
the illness can be inferred. In perplexing cases it is useful 
to remember that uncommon presentations of common 



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10 



TABLE 1-2 



FINDINGS HELPFUL FOR LOCALIZATION WITHIN THE NERVOUS SYSTEM 



Cerebrum 



o 



o 
o 

CD 



O 



Brainstem 



Spinal cord 



Spinal roots 



Peripheral nerve 



Neuromuscular 
junction 

Muscle 



SIGNS 

Abnormal mental status or cognitive impairment 

Seizures 

Unilateral weakness 3 and sensory abnormalities including 

head and limbs 
Visual field abnormalities 
Movement abnormalities (e.g., diffuse incoordination, 

tremor, chorea) 

Isolated cranial nerve abnormalities (single or multiple) 
"Crossed" weakness 3 and sensory abnormalities of head 

and limbs (e.g., weakness of right face and left arm and leg) 
Back pain or tenderness 

Weakness 3 and sensory abnormalities sparing the head 
Mixed upper and lower motor neuron findings 
Sensory level 
Sphincter dysfunction 
Radiating limb pain 
Weakness" or sensory abnormalities following root 

distribution (see Figs. 12-2 and 12-3) 
Loss of reflexes 
Mid or distal limb pain 
Weakness" or sensory abnormalities following nerve 

distribution (see Figs. 12-2 and 12-3) 
"Stocking or glove" distribution of sensory loss 
Loss of reflexes 
Bilateral weakness including face (ptosis, diplopia, 

dysphagia) and proximal limbs 
Increasing weakness with exertion 
Sparing of sensation 
Bilateral proximal or distal weakness 
Sparing of sensation 



a Weakness along with other abnormalities having an "upper motor neuron" pattern (i.e., spas- 
ticity, weakness of extensors > flexors in the upper extremity and flexors > extensors in the 
lower extremity, hyperreflexia). 

^Weakness along with other abnormalities having a "lower motor neuron" pattern (i.e., flaccidity 
and hyporeflexia). 



diseases are more likely than rare etiologies. Thus, even 
in tertiary care settings, multiple strokes are usually due 
to emboli and not vasculitis, and dementia with 
myoclonus is usually Alzheimer's disease and not due to 
a prion disorder or a paraneoplastic cause. Finally, the 
most important task of a primary care physician faced 
with a patient who has a new neurologic complaint is to 
assess the urgency of referral to a specialist. Here, the 
imperative is to rapidly identify patients likely to have 
nervous system infections, acute strokes, and spinal cord 



compression or other treatable mass lesions and arrange 
for immediate care. 

FURTHER READINGS 

BLUMENTHAL H: Neuroanatomy Through Clinical Cases, 2d ed. Sunder- 
land, Massachusetts, Sinauer Associates, 2010 

CAMPBELL WW: Dejong's The Neurological Examination, 6th ed. 
Philadelphia, Lippincott Williams & Wilkins, 2005 

Ropper AH, Samuels MA: Principles of Neurology, 9th ed. New York, 
McGraw-Hill, 2009 




William P. Dillon 



Computed Tomography 11 

Technique 11 

Indications 13 

Complications 13 

Magnetic Resonance Imaging 15 

Technique 15 

Complications and Contraindications 17 

Magnetic Resonance Angiography 18 

Echo-Planar MR Imaging 20 

Magnetic Resonance Neurography 21 

Positron Emission Tomography (PET) 21 

Myelography 21 



Technique 21 

Indications 21 

Contraindications 22 

Complications 22 

Spine Interventions 22 

Discography 22 

Selective Nerve Root and Epidural Spinal Injections 22 

Angiography 22 

Complications 23 

Spinal Angiography 23 

Interventional Neuroradiology 23 

Further Readings 23 



The clinician caring for patients with neurologic symp- 
toms is faced with an expanding number of imaging 
options, including computed tomography (CT), CT 
angiography (CTA), perfusion CT (pCT), magnetic 
resonance imaging (MRI), MR angiography (MRA), 
functional MRI (fMRI), MR spectroscopy (MRS), MR 
neurography, diffusion and diffusion track imaging 
(DTI), and perfusion MRI (pMRI). In addition, an 
increasing number of interventional neuroradiologic 
techniques are available, including angiography; emboliza- 
tion, coiling, and stenting of vascular structures; and 
spine interventions such as discography, selective nerve 
root injection, and epidural injections. Recent develop- 
ments, such as multidetector CTA and gadolinium- 
enhanced MRA, have narrowed the indications for con- 
ventional angiography, which is now reserved for 
patients in whom small-vessel detail is essential for diag- 
nosis or for whom interventional therapies are planned 
(Table 2-1). 

In general, MRI is more sensitive than CT for the 
detection of lesions affecting the central nervous system 
(CNS), particularly those of the spinal cord, cranial 
nerves, and posterior fossa structures. Diffusion MR, a 
sequence that detects reduction of microscopic motion 
of water, is the most sensitive technique for detecting 



11 



acute ischemic stroke and is also useful in the detection 
of encephalitis, abscesses, and prion diseases. CT, how- 
ever, can be quickly obtained and is widely available, 
making it a pragmatic choice for the initial evaluation of 
patients with acute changes in mental status, suspected 
acute stroke, hemorrhage, and intracranial or spinal 
trauma. CT is also more sensitive than MRI for visualiz- 
ing fine osseous detail and is indicated in the initial eval- 
uation of conductive hearing loss as well as lesions 
affecting the skull base and calvarium. 

COMPUTED TOMOGRAPHY 

TECHNIQUE 

The CT image is a cross-sectional representation of 
anatomy created by a computer-generated analysis of the 
attenuation of x-ray beams passed through a section of 
the body. As the x-ray beam, colhmated to the desired 
slice width, rotates around the patient, it passes through 
selected regions in the body. X-rays that are not attenu- 
ated by the body are detected by sensitive x-ray detectors 
aligned 180° from the x-ray tube. A computer calculates 
a "back projection" image from the 360° x-ray attenua- 
tion profile. Greater x-ray attenuation, e.g., as caused by 



12 



TABLE 2-1 



GUIDELINES FOR THE USE OF CT, ULTRASOUND, AND MRI 



o 



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CD 



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CONDITION 


RECOMMENDED TECHNIQUE 


Hemorrhage 




Acute parenchymal 


CT, MR 


Subacute/chronic 


MRI 


Subarachnoid hemorrhage 


CT, CTA, lumbar puncture — > angiography 


Aneurysm 


Angiography > CTA, MRA 


Ischemic infarction 




Hemorrhagic infarction 


CT or MRI 


Bland infarction 


MRI > CT, CTA, angiography 


Carotid or vertebral dissection 


MRI/MRA 


Vertebral basilar insufficiency 


CTA, MRI/MRA 


Carotid stenosis 


CTA > Doppler ultrasound, MRA 


Suspected mass lesion 




Neoplasm, primary or metastatic 


MRI + contrast 


Infection/abscess 


MRI + contrast 


Immunosuppressed with focal findings 


MRI + contrast 


Vascular malformation 


MRI +/- angiography 


White matter disorders 


MRI 


Demyelinating disease 


MRI +/- contrast 


Dementia 


MRI > CT 


Trauma 




Acute trauma 


CT (noncontrast) 


Shear injury/chronic hemorrhage 


MRI 


Headache/migraine 


CT (noncontrast) / MRI 


Seizure 




First time, no focal neurologic deficits 


CT as screen +/- contrast 


Partial complex/refractory 


MRI with coronal T2W imaging 


Cranial neuropathy 


MRI with contrast 


Meningeal disease 


MRI with contrast 


Spine 




Low back pain 




No neurologic deficits 


MRI or CT after 4 weeks 


With focal deficits 


MRI > CT 


Spinal stenosis 


MRI or CT 


Cervical spondylosis 


MRI or CT myelography 


Infection 


MRI + contrast, CT 


Myelopathy 


MRI + contrast > myelography 


Arteriovenous malformation 


MRI, myelography/angiography 



Note: CT, computed tomography; MRI, magnetic resonance imaging; MRA, MR angiography; CTA, CT 
angiography; T2W, T2-weighted. 



bone, results in areas of high "density," -whereas soft tissue 
structures, -which have poor attenuation of x-rays, are 
lower in density. The resolution of an image depends on 
the radiation dose, the detector size or collimation (slice 
thickness), the field of view, and the matrix size of the 
display. A modern CT scanner is capable of obtaining 
sections as thin as 0.5—1 mm with submillimeter resolu- 
tion at a speed of 0.5-1 s per rotation; complete studies 
of the brain can be completed in 2-10 s. 

Helical or multidetector CT (MDCT) is now stan- 
dard in most radiology departments. Continuous CT 
information is obtained while the patient moves through 
the x-ray beam. In the helical scan mode, the table moves 
continuously through the rotating x-ray beam, generating 



a "helix" of information that can be reformatted into 
various slice thicknesses. Single or multiple (from 4 to 256) 
detectors positioned 180° to the x-ray source may result 
in multiple slices per revolution of the beam around the 
patient. Advantages of MDCT include shorter scan 
times, reduced patient and organ motion, and the ability 
to acquire images dynamically during the infusion of 
intravenous contrast that can be used to construct CT 
angiograms of vascular structures and CT perfusion 
images (Figs. 2-1B, 2-2B, and 2-3B). CTA images are 
post-processed for display in three dimensions to yield 
angiogram-like images (Fig. 2-1C and see Fig. 21-4). 
CTA has proved useful in assessing the cervical and 
intracranial arterial and venous anatomy. 




FIGURE 2-1 

CT angiography (CTA) of ruptured anterior cerebral artery 
aneurysm in a patient presenting with acute headache. 

A. Noncontrast CT demonstrates subarachnoid hemorrhage 
and mild obstructive hydrocephalus. B. Axial maximum 
intensity projection from CT angiography demonstrates 
enlargement of the anterior cerebral artery (arrow). C. 3D sur- 
face reconstruction using a workstation confirms the anterior 
cerebral aneurysm and demonstrates its orientation and rela- 
tionship to nearby vessels (arrow). CTA image is produced by 
0.5-1 mm helical CT scans performed during a rapid bolus 
infusion of intravenous contrast medium. 



Intravenous iodinated contrast is often administered 
prior to or during a CT study to identify vascular struc- 
tures and to detect defects in the blood-brain barrier 
(BBB) that are associated with disorders such as tumors, 
infarcts, and infections. In the normal CNS, only vessels 
and structures lacking a BBB (e.g., the pituitary gland, 
choroid plexus, and dura) enhance after contrast admin- 
istration. The use of iodinated contrast agents carries a 
risk of allergic reaction and adds additional expense and 
radiation dose. Although helpful in characterizing mass 
lesions as well as essential for the acquisition of CTA 
studies, the decision to use contrast material should 
always be considered carefully. 

INDICATIONS 

CT is the primary study of choice in the evaluation of 
an acute change in mental status, focal neurologic find- 
ings, acute trauma to the brain and spine, suspected sub- 
arachnoid hemorrhage, and conductive hearing loss 
(Table 2-1). CT is complementary to MR in the evalua- 
tion of the skull base, orbit, and osseous structures of the 
spine. In the spine, CT is useful in evaluating patients 
with osseous spinal stenosis and spondylosis, but MRI is 
often preferred in those with neurologic deficits. CT 
can also be obtained following intrathecal contrast injec- 
tion to evaluate the intracranial cisterns (CT cisternogra- 
phy) for cerebrospinal fluid (CSF) fistula, as well as the 
spinal subarachnoid space (CT myelography). 

COMPLICATIONS 

CT is safe, fast, and reliable. Radiation exposure depends 
on the dose used but is normally between 3 and 5 cGy 
for a routine brain CT study. Care must be taken to 
reduce exposure when imaging children. With the 
advent of MDCT, CTA, and CT perfusion, care must be 
taken to appropriately minimize radiation dose when- 
ever possible. The most frequent complications are asso- 
ciated with use of intravenous contrast agents. Two 
broad categories of contrast media, ionic and nonionic, 
are in use. Although ionic agents are relatively safe and 
inexpensive, they are associated with a higher incidence 
of reactions and side effects (Table 2-2). As a result, 
ionic agents have been largely replaced by safer nonionic 
compounds. 

Contrast nephropathy may result from hemodynamic 
changes, renal tubular obstruction and cell damage, or 
immunologic reactions to contrast agents. A rise in 
serum creatinine of at least 85 (Xmol/L (1 mg/dL) 
within 48 h of contrast administration is often used as a 
definition of contrast nephropathy, although other 
causes of acute renal failure must be excluded. The prog- 
nosis is usually favorable, with serum creatinine levels 
returning to baseline within 1—2 weeks. Risk factors for 
contrast nephropathy include advanced age (>80 years), 



13 



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FIGURE 2-2 

Acute left hemiparesis due to middle cerebral artery 
occlusion. A. Axial noncontrast CT scan demonstrates high 
density within the right middle cerebral artery (arrow) associ- 
ated with subtle low density involving the right putamen 
(arrowheads). B. Mean transit time map calculated from a CT 
perfusion study; prolongation of the mean transit time is visi- 
ble throughout the right hemisphere (arrows). C. Axial maxi- 
mum intensity projection from a CTA study through the Circle 
of Willis demonstrates an abrupt occlusion of the proximal 



right middle cerebral artery (arrow). Reconstitution of flow via 
collaterals is seen distal to the occlusion; however, the 
patient sustained a right basal ganglia infarction. D. Sagittal 
reformation through the right internal carotid artery demon- 
strates a low-density lipid laden plaque (arrowheads) narrow- 
ing the lumen (black arrow) E. 3D surface CTA images from a 
different patient demonstrate calcification and narrowing of 
the right internal carotid artery (arrow), consistent with ather- 
osclerotic disease. 



TABLE 2-2 



GUIDELINES FOR USE OF INTRAVENOUS CONTRAST 
IN PATIENTS WITH IMPAIRED RENAL FUNCTION 



SERUM CREATININE, 




Xmol/L (mg/dL) 3 


RECOMMENDATION 


<133(<1.5) 


Use either ionic or nonionic at 




2mLVkgto150mLtotal 


133-177(1.5-2.0) 


Nonionic; hydrate diabetics 




1 mLVkg per hour x 1 h 


>177(>2.0) 


Consider noncontrast CT or MRI; 




nonionic contrast if required 


177-221 (2.0-2.5) 


Nonionic only if required (as above); 




contraindicated in diabetics 


>265 (>3.0) 


Nonionic IV contrast given only to 




patients undergoing dialysis within 




24 h 



a Risk is greatest in patients with rising creatinine levels. 

Note: CT, computed tomography; MRI, magnetic resonance imaging. 



preexisting renal disease (serum creatinine exceeding 
2.0 mg/dL), solitary kidney, diabetes mellitus, dehydration, 
paraproteinemia, concurrent use of nephrotoxic medica- 
tion or chemotherapeutic agents, and high contrast dose. 
Patients with diabetes and those with mild renal failure 
should be well hydrated prior to the administration of 
contrast agents, although careful consideration should be 
given to alternative imaging techniques, such as MR 
imaging or noncontrast examinations. Nonionic, low- 
osmolar media produce fewer abnormalities in renal 
blood flow and less endothelial cell damage but should 
still be used carefully in patients at risk for allergic reac- 
tion (Table 2-3). 

Other side effects are rare but include a sensation of 
warmth throughout the body and a metallic taste during 
intravenous administration of iodinated contrast media. 
The most serious side effects are anaphylactic reactions, 

TABLE 2-3 



INDICATIONS FOR USE OF NONIONIC CONTRAST 
MEDIA 



Prior adverse reaction to contrast media, with the 
exception of heat, flushing, or an episode of nausea or 
vomiting 

Asthma or other serious lung disease 
History of atopic allergies (pretreatment with 
steroid/antihistamines recommended) 
Children younger than 2 years 
Renal failure or creatinine >177 u.mol/L (>2.0 mg/dL) 
Cardiac dysfunction, including recent or imminent car- 
diac decompensation, severe arrhythmias, unstable 
angina pectoris, recent myocardial infarction, and pul- 
monary hypertension 
Diabetes 
Severe debilitation 



TABLE 2-4 15 



GUIDELINES FOR PREMEDICATION OF PATIENTS 
WITH PRIOR CONTRAST ALLERGY 



12 h prior to examination: 

Prednisone, 50 mg PO or methylprednisolone, 32 mg PO 
2 h prior to examination: 
Prednisone, 50 mg PO or methylprednisolone, 
32 mg PO and 

Cimetidine, 300 mg PO or ranitidine, 150 mg PO 

Immediately prior to examination: ^ 

Benadryl, 50 mg IV (alternatively, can be given PO 2 h 2 

prior to exam) o 

3' 

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which range from mild hives to bronchospasm, acute 
anaphylaxis, and death. The pathogenesis of these allergic 
reactions is not fully understood but is thought to 
include the release of mediators such as histamine, 
antibody-antigen reactions, and complement activation. 
Severe allergic reactions occur in ~0.04% of patients 
receiving nonionic media, sixfold fewer than with ionic 
media. Risk factors include a history of prior contrast 
reaction, food allergies to shellfish, and atopy (asthma 
and hay fever). In such patients, a noncontrast CT or 
MRI procedure should be considered as an alternative 
to contrast administration. If iodinated contrast is 
absolutely required, a nonionic agent should be used in 
conjunction with pretreatment with glucocorticoids and 
antihistamines (Table 2-4). Patients with allergic reac- 
tions to iodinated contrast material do not usually react 
to gadolinium-based MR contrast material, although 
such reactions do occur. It would be wise to pretreat 
patients with a prior allergic history to MR contrast 
administration in a similar fashion. 



MAGNETIC RESONANCE IMAGING 

TECHNIQUE 

Magnetic resonance is a complex interaction between 
hydrogen protons in biologic tissues, a static magnetic 
field (the magnet), and energy in the form of radiofre- 
quency (Rf) waves of a specific frequency introduced by 
coils placed next to the body part of interest. Field 
strength of the magnet is directly related to signal-to- 
noise ratio. Although 1.5 Telsa magnets have become the 
standard high-field MRI units, 3T— 8T magnets are now 
available and have distinct advantages in the brain and 
musculoskeletal systems. Spatial localization is achieved by 
magnetic gradients surrounding the main magnet, which 
impart slight changes in magnetic field throughout the 
imaging volume. The energy state of the hydrogen pro- 
tons is transiently excited by Rf, which is administered at 
a frequency specific for the field strength of the magnet. 
The subsequent return to equilibrium energy state 



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16 



o 



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(relaxation) of the protons results in a release of Rf energy 
(the echo), which is detected by the coils that delivered the 
Rf pulses. The echo is transformed by Fourier analysis 
into the information used to form an MR image. The 
MR image thus consists of a map of the distribution of 
hydrogen protons, with signal intensity imparted by both 
density of hydrogen protons and differences in the relax- 
ation times (see below) of hydrogen protons on different 
molecules. Although clinical MRI currently makes use of 
the ubiquitous hydrogen proton, research into sodium 
and carbon imaging appears promising. 

T1 and T2 Relaxation Times 

The rate of return to equilibrium of perturbed protons 
is called the relaxation rate. The relaxation rate varies 
among normal and pathologic tissues. The relaxation 
rate of a hydrogen proton in a tissue is influenced by 
local interactions with surrounding molecules and 
atomic neighbors. Two relaxation rates, Tl andT2, influ- 
ence the signal intensity of the image. The Tl relaxation 
time is the time, measured in milliseconds, for 63% of 
the hydrogen protons to return to their normal equilib- 
rium state, while the T2 relaxation is the time for 63% 
of the protons to become dephased owing to interac- 
tions among nearby protons. The intensity of the signal 
within various tissues and image contrast can be modu- 
lated by altering acquisition parameters, such as the 
interval between Rf pulses (TR) and the time between 
the Rf pulse and the signal reception (TE). So-called 
Tl -weighted (T1W) images are produced by keeping 
the TR and TE relatively short. T2-weighted (T2W) 
images are produced by using longer TR and TE times. 
Fat and subacute hemorrhage have relatively shorter Tl 
relaxation rates and thus higher signal intensity than 
brain on T1W images. Structures containing more 
water, such as CSF and edema, have long Tl and T2 
relaxation rates, resulting in relatively lower signal inten- 
sity on T1W images and a higher signal intensity on 
T2W images (Table 2-5). Gray matter contains 10—15% 
more water than white matter, which accounts for much 
of the intrinsic contrast between the two on MRI 



TABLE 2-5 



SOME COMMON INTENSITIES ON T1- AND 
T2-WEIGHTED MRI SEQUENCES 



SIGNAL INTENSITY 



IMAGE 


TR 


TE 


CSF 


FAT 


BRAIN 


EDEMA 


T1W 
T2W 


Short 
Long 


Short 
Long 


Low 
High 


High 
Low 


Low 
High 


Low 
High 



Note: TR, interval between radiofrequency (Rf) pulses; TE, interval 
between Rf pulse and signal reception; CSF, cerebrospinal fluid; 
T1W and T2W, T1- and T2 -weighted. 



(Fig. 2-3). T2W images are more sensitive than T1W 
images to edema, demyelination, infarction, and chronic 
hemorrhage, whereas T1W imaging is more sensitive to 
subacute hemorrhage and fat-containing structures. 

Many different MR pulse sequences exist, and each 
can be obtained in various planes (Figs. 2-3, 2-4, 2-5). 
The selection of a proper protocol that will best answer 
a clinical question depends on an accurate clinical history 
and indication for the examination. Fluid-attenuated 
inversion recovery (FLAIR) is a useful pulse sequence 
that produces T2W images in which the normally high 
signal intensity of CSF is suppressed (Fig. 2-5 A). FLAIR 
images are more sensitive than standard spin echo images 
for any water-containing lesions or edema. Gradient 
echo imaging is most sensitive to magnetic susceptibility 
generated by blood, calcium, and air and is indicated in 
patients with traumatic brain injury to assess for subtle 
contusions and shear microhemorrhages. MR images 
can be generated in any plane without changing the 
patient's position. Each sequence, however, must be 
obtained separately and takes 1—5 min on average to 
complete. Three-dimensional volumetric imaging is also 
possible with MRI, resulting in a volume of data that 
can be reformatted in any orientation on a workstation 
to highlight certain disease processes. 

MR Contrast Material 

The heavy-metal element gadolinium forms the basis 
of all currently approved intravenous MR contrast 
agents. Gadolinium is a paramagnetic substance, which 
means that it reduces the Tl andT2 relaxation times of 
nearby water protons, resulting in a high signal on Tl W 
images and a low signal on T2W images (the latter 
requires a sufficient local concentration, usually in the 
form of an intravenous bolus). Unlike iodinated con- 
trast agents, the effect of MR contrast agents depends 
on the presence of local hydrogen protons on which it 
must act to achieve the desired effect. Gadolinium is 
chelated to DTPA (diethylenetriaminepentaacetic acid), 
which allows safe renal excretion. Approximately 0.2 
mL/kg body weight is administered intravenously; the 
cost is ~$60 per dose. Gadolinium-DTPA does not nor- 
mally cross the intact BBB immediately but will 
enhance lesions lacking a BBB (Fig. 2-4A) and areas of 
the brain that normally are devoid of the BBB (pitu- 
itary, choroid plexus) . However, gadolinium contrast has 
been noted to slowly cross an intact BBB if given over 
time and especially in the setting of reduced renal 
clearance. The agents are generally well tolerated; severe 
allergic reactions are rare but have been reported. The 
adverse reaction rate in patients with a prior history of 
atopy or asthma is 3.7%; however, the reaction rate 
increases to 6.3% in those patients with a prior history 
of unspecified allergic reaction to iodinated contrast 
agents. Gadolinium contrast material can be administered 




17 



FIGURE 2-3 

A. Axial noncontrast CT scan in a patient with left hemipare- 
sis shows a subtle low density involving the right temporal 
and frontal lobes (arrows). The hyperdense middle cerebral 
artery (arrowhead) indicates an embolic occlusion of the mid- 
dle cerebral artery. B. Mean transit time CT perfusion para- 
metric map indicating prolonged mean transit time involving 
the right middle cerebral territory (arrows). C. Cerebral blood 



volume map shows reduced CBV involving an area within the 
defect shown in B, indicating infarction (arrows). D. Coronal 
maximum intensity projection from MRA shows right middle 
cerebral artery (MCA) occlusion (arrow). E and F. Axial diffu- 
sion weighted image (£) and apparent diffusion coefficient 
image (F) documents the presence of a right middle cerebral 
artery infarction. 



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safely to children as well as adults, although these agents 
are generally avoided in those younger than 6 months. 
Renal failure does not occur. 

A rare complication, nephrogenic systemic fibrosis 
(NSF), has recently been reported in patients with renal 
insufficiency, who have been exposed to gadolinium 
contrast agents. The onset of NSF has been reported 
between 5 and 75 days following exposure; histologic fea- 
tures include thickened collagen bundles with surrounding 
clefts, mucin deposition, and increased numbers of 
fibrocytes and elastic fibers in skin. In addition to 
dermatologic symptoms, other manifestations include 



widespread fibrosis of the skeletal muscle, bone, lungs, 
pleura, pericardium, myocardium, kidney, muscle, bone, 
testes, and dura. 



COMPLICATIONS AND CONTRAINDICATIONS 

From the patient's perspective, an MRI examination can 
be intimidating, and a higher level of cooperation is 
required than with CT. The patient lies on a table that is 
moved into a long, narrow gap within the magnet. 
Approximately 5% of the population experiences severe 



18 



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FIGURE 2-4 

Cerebral abscess in a patient with fever and 
a right hemiparesis. A. Coronal postcontrast 
T1 -weighted image demonstrates a ring enhanc- 
ing mass in the left frontal lobe. B. Axial 
diffusion-weighted image demonstrates restricted 
diffusion (high signal intensity) within the lesion, 
which in this setting is highly suggestive of 
cerebral abscess. C. Single voxel proton spec- 
troscopy (TE of 288 ms) reveals a reduced Naa 
peak and abnormal peaks for acetate, alanine 
(Ala), lactate (Lac), and amino acids (AA). These 
findings are highly suggestive of cerebral 
abscess; at biopsy a streptococcal abscess 
was identified. 



claustrophobia in the MR environment. This can be 
reduced by mild sedation but remains a problem for 
some. Unlike CT, movement of the patient during an 
MR sequence distorts all the images; therefore, uncoop- 
erative patients should either be sedated for the MR study 
or scanned with CT. Generally children younger than 
10 years usually require conscious sedation in order to com- 
plete the MR examination without motion degradation. 

MRI is considered safe for patients, even at very high 
field strengths (>3— 4 T). Serious injuries have been 
caused, however, by attraction of ferromagnetic objects 
into the magnet, which act as missiles if brought too 
close to the magnet. Likewise, ferromagnetic implants, 
such as aneurysm clips, may torque within the magnet, 
causing damage to vessels and even death. Metallic for- 
eign bodies in the eye have moved and caused intraocu- 
lar hemorrhage; screening for ocular metallic fragments 



is indicated in those with a history of metal work or 
ocular metallic foreign bodies. Implanted cardiac pace- 
makers are generally a contraindication to MRI owing 
to the risk of induced arrhythmias; however, some 
newer pacemakers have been shown to be safe. All 
health care personnel and patients must be screened and 
educated thoroughly to prevent such disasters as the 
magnet is always "on." Table 2-6 lists common con- 
traindications for MRI. 



MAGNETIC RESONANCE 
ANGIOGRAPHY 

MR angiography (MRA) is a general term describing sev- 
eral MR techniques that result in vascular-weighted 
images. These provide a vascular flow map rather than 




19 



FIGURE 2-5 

Herpes simplex encephalitis in a patient presenting with 
altered mental status and fever. A. Coronal T2-weighted 
FLAIR image demonstrates expansion and high signal intensity 
involving the left medial temporal lobe, insular cortex, and left 
cingulate gyrus. B. Diffusion-weighted image demonstrates 
high signal intensity indicating restricted diffusion involving the 



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left medial temporal lobe and hippocampus (arrows). This is 
most consistent with neuronal death and can be seen in acute 
infarction as well as encephalitis and other inflammatory con- 
ditions. The suspected diagnosis of herpes simplex encephali- 
tis was confirmed by CSF PCR analysis. (Courtesy of Howard 
Rowley, MD, University of Wisconsin; with permission.) 



o 



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ro 



the anatomic map shown by conventional angiography. 
On routine spin echo MR sequences, moving protons 
(e.g., flowing blood, CSF) exhibit complex MR signals 
that range from high to low signal intensity relative to 
background stationary tissue. Fast-flowing blood returns 
no signal (flow void) on routine T1W or T2W spin 
echo MR images. Slower-flowing blood, as occurs in 
veins or distal to arterial stenosis, may appear high in 
signal. However, using special pulse sequences called gra- 
dient echo sequences, it is possible to increase the signal 

TABLE 2-6 



COMMON CONTRAINDICATIONS TO MR IMAGING 



Cardiac pacemaker or permanent pacemaker leads 

Internal defibrillator device 

Cochlear prostheses 

Bone growth stimulators 

Spinal cord stimulators 

Electronic infusion devices 

Intracranial aneurysm clips (some but not all) 

Ocular implants (some) or ocular metallic foreign body 

McGee stapedectomy piston prosthesis 

Omniphase penile implant 

Swan-Ganz catheter 

Magnetic stoma plugs 

Magnetic dental implants 

Magnetic sphincters 

Ferromagnetic IVC filters, coils, stents — safe 6 weeks 

after implantation 
Tattooed eyeliner (contains ferromagnetic material and 

may irritate eyes) 



intensity of moving protons in contrast to the low signal 
background intensity of stationary tissue. This creates 
angiography-like images, which can be manipulated in 
three dimensions to highlight vascular anatomy and 
relationships. 

Time-of-flight (TOF) imaging, currently the tech- 
nique used most frequently, relies on the suppression of 
nonmoving tissue to provide a low-intensity back- 
ground for the high signal intensity of flowing blood 
entering the section; arterial or venous structures may 
be highlighted. A typical TOF angiography sequence 
results in a series of contiguous, thin MR sections 
(0.6—0.9 mm thick), which can be viewed as a stack and 
manipulated to create an angiographic image data set 
that can be reformatted and viewed in various planes 
and angles, much like that seen with conventional 
angiography (Fig. 2-3D). 

Phase-contrast MRA has a longer acquisition time 
than TOF MRA, but in addition to providing anatomic 
information similar to that of TOF imaging, it can be 
used to reveal the velocity and direction of blood flow 
in a given vessel. Through the selection of different 
imaging parameters, differing blood velocities can be 
highlighted; selective venous and arterial MRA images 
can thus be obtained. One advantage of phase-contrast 
MRA is the excellent suppression of high signal inten- 
sity background structures. 

MRA can also be acquired during infusion of con- 
trast material. Advantages include faster imaging times 
(1—2 min vs. 10 min), fewer flow-related artifacts, and 
higher-resolution images. Recently, contrast-enhanced 



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MRA has become the standard for extracranial vascular 
MRA. This technique entails rapid imaging using coro- 
nal three-dimensional TOF sequences during a bolus 
infusion of 15—20 mL of gadolinium-DTPA. Proper 
technique and timing of acquisition relative to bolus 
arrival are critical for success. 

MRA has lower spatial resolution compared with 
conventional film-based angiography, and therefore the 
detection of small-vessel abnormalities, such as vasculitis 
and distal vasospasm, is problematic. MRA is also less 
sensitive to slowly flowing blood and thus may not reli- 
ably differentiate complete from near-complete occlu- 
sions. Motion, either by the patient or by anatomic 
structures, may distort the MRA images, creating arti- 
facts. These limitations notwithstanding, MRA has 
proved useful in evaluation of the extracranial carotid 
and vertebral circulation as well as of larger-caliber 
intracranial arteries and dural sinuses. It has also proved 
useful in the noninvasive detection of intracranial 
aneurysms and vascular malformations. 



ECHO-PLANAR MR IMAGING 

Recent improvements in gradients, software, and high- 
speed computer processors now permit extremely rapid 
MRI of the brain. With echo-planar MRI (EPI), fast 
gradients are switched on and off at high speeds to cre- 
ate the information used to form an image. In routine 
spin echo imaging, images of the brain can be obtained 
in 5—10 min. With EPI, all of the information required 



for processing an image is accumulated in 50—150 ms, 
and the information for the entire brain is obtained in 
1—2 min, depending on the degree of resolution 
required or desired. Fast MRI reduces patient and organ 
motion, permitting diffusion imaging and tractography 
(Figs. 2-3, 2-4, 2-5, 2-6; and see Fig. 21-16), perfusion 
imaging during contrast infusion, fMRI, and kinematic 
motion studies. 

Perfusion and diffusion imaging are EPI techniques 
that are useful in early detection of ischemic injury of 
the brain and may be useful together to demonstrate 
infarcted tissue as well as ischemic but potentially viable 
tissue at risk of infarction (e.g., the ischemic penumbra). 
Diffusion-weighted imaging (DWI) assesses microscopic 
motion of water; restriction of motion appears as relative 
high signal intensity on diffusion-weighted images. DWI 
is the most sensitive technique for detection of acute 
cerebral infarction of <7 days' duration and is also sensi- 
tive to encephalitis and abscess formation, all of which 
have reduced diffusion and result in high signal on diffu- 
sion-weighted images. 

Perfusion MRI involves the acquisition of EPI images 
during a rapid intravenous bolus of gadolinium contrast 
material. Relative perfusion abnormalities can be identi- 
fied on images of the relative cerebral blood volume, 
mean transit time, and cerebral blood flow. Delay in 
mean transit time and reduction in cerebral blood vol- 
ume and cerebral blood flow are typical of infarction. In 
the setting of reduced blood flow, a prolonged mean 
transit time of contrast but normal or elevated cerebral 
blood volume may indicate tissue supplied by collateral 




A B 

FIGURE 2-6 

Diffusion tractography in cerebral glioma. A. An axial fast 
spin echo T2-weighted image shows a high signal intensity 
glioma of the insular cortex lateral to the fibers of the internal 
capsule. B and C. Axial post-gadolinium images with diffusion 



tractography superimposed on the image. This shows the 
position of the internal capsule (arrows) relative to the enhanc- 
ing tumor. 



flow that is at risk of infarction. pMRI imaging can also 
be used in the assessment of brain tumors to differenti- 
ate intraaxial primary tumors from extraaxial tumors or 
metastasis. 

Diffusion tract imaging (DTI) is derived from diffu- 
sion MRI techniques. Preferential microscopic motion 
of water along white matter tracts is detected by diffu- 
sion MR, which can also indicate the direction of white 
matter fiber tracts. This new technique has great poten- 
tial in the assessment of brain maturation as well as dis- 
ease entities that undermine the integrity of the white 
matter architecture (Fig. 2-7). 

fMRI of the brain is an EPI technique that localizes 
regions of activity in the brain following task activation. 
Neuronal activity elicits a slight increase in the delivery 
of oxygenated blood flow to a specific region of acti- 
vated brain. This results in an alteration in the balance of 
oxyhemoglobin and deoxyhemoglobin, which yields a 
2—3% increase in signal intensity within veins and local 
capillaries. Further studies will determine whether these 
techniques are cost-effective or clinically useful, but cur- 
rently preoperative somatosensory and auditory cortex 
localization is possible. This technique has proved useful 
to neuroscientists interested in interrogating the local- 
ization of certain brain functions. 



MAGNETIC RESONANCE 
NEUROGRAPHY 



21 




FIGURE 2-7 

Diffusion tractography in a healthy individual obtained at 
3T demonstrates the normal subcortical fiber pathways. The 
direction of the tracts have been color-coded (red, left-right; 
green, anterior-posterior; blue, superior-inferior). (Courtesy of 
Pratik Mukherjee, MD, PhD; with permission.) 



MR neurography is an MR technique that shows promise 
in detecting increased signal in irritated, inflamed, or 
infiltrated peripheral nerves. Images are obtained with 
fat-suppressed fast spin echo imaging or short inversion 
recovery sequences. Irritated or infiltrated nerves will 
demonstrate high signal on T2W imaging. 



POSITRON EMISSION 

TOMOGRAPHY (PET) 

PET relies on the detection of positrons emitted during 
the decay of a radionuclide that has been injected into a 
patient. The most frequently used moiety is 2-[ 18 F] 
fluoro-2-deoxy-D-glucose (FDG), which is an ana- 
logue of glucose and is taken up by cells competitively 
with 2-deoxyglucose. Multiple images of glucose 
uptake activity are formed after 45—60 min. Images 
reveal differences in regional glucose activity among 
normal and pathologic brain structures. A lower activity 
of FDG in the parietal lobes has been associated with 
Alzheimer's disease. FDG PET is used primarily for the 
detection of extracranial metastatic disease. Combina- 
tion PET-CT scanners, in which both CT and PET are 
obtained at one sitting, are replacing PET scans alone 
for most clinical indications. Functional images super- 
imposed on high-resolution CT scans result in more 
precise anatomic diagnoses. 

MYELOGRAPHY 

TECHNIQUE 

Myelography involves the intrathecal instillation of spe- 
cially formulated water-soluble iodinated contrast 
medium into the lumbar or cervical subarachnoid space. 
CT scanning is usually performed after myelography 
(CT myelography) to better demonstrate the spinal cord 
and roots, which appear as filling defects in the opacified 
subarachnoid space. Low-dose CT myelography, in which 
CT is performed after the subarachnoid injection of a 
small amount of relatively dilute contrast material, has 
replaced conventional myelography for many indica- 
tions, thereby reducing exposure to radiation and con- 
trast media. Newer multidetector scanners now obtain 
CT studies quickly so that reformations in sagittal and 
coronal planes, equivalent to traditional myelography 
projections, are now routine. 

INDICATIONS 

Myelography has been largely replaced by CT myelog- 
raphy and MRI for diagnosis of diseases of the spinal 



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22 canal and cord (Table 2-1). Remaining indications for 
conventional plain-film myelography include the evalu- 
ation of suspected meningeal or arachnoid cysts and the 
localization of spinal dural arteriovenous or CSF fistulas. 
Conventional myelography and CT myelography pro- 
vide the most precise information in patients with prior 
spinal fusion and spinal fixation hardware. 



ET CONTRAINDICATIONS 



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Myelography is relatively safe; however, it should be per- 
formed with caution in any patient -with elevated 
intracranial pressure, evidence of a spinal block, or a his- 
tory of allergic reaction to intrathecal contrast media. In 
patients with a suspected spinal block, MR is the pre- 
ferred technique. If myelography is necessary, only a 
small amount of contrast medium should be instilled 
below the lesion in order to minimize the risk of neuro- 
logic deterioration. Lumbar puncture is to be avoided in 
patients with bleeding disorders, including patients 
receiving anticoagulant therapy, as well as in those with 
infections of the soft tissues. 



COMPLICATIONS 

Headache, nausea, and vomiting are the most frequent 
complications of myelography and are reported to occur 
in up to 38% of patients. These symptoms result from 
either neurotoxic effects of the contrast agent, persistent 
leakage of CSF at the puncture site, or psychological 
reactions to the procedure. Vasovagal syncope may occur 
during lumbar puncture; it is accentuated by the upright 
position used during lumbar myelography. Adequate 
hydration before and after myelography will reduce the 
incidence of this complication. Postural headache 
(post— lumbar puncture headache) is generally due to 
leakage of CSF from the puncture site, resulting in CSF 
hypotension. Management of post-lumbar-puncture 
headache is discussed in Chap. 4. 

If significant headache persists for longer than 48 hours, 
placement of an epidural blood patch should be consid- 
ered. Hearing loss is a rare complication of myelography. 
It may result from a direct toxic effect of the contrast 
medium or from an alteration of the pressure equilib- 
rium between CSF and perilymph in the inner ear. 
Puncture of the spinal cord is a rare but serious compli- 
cation of cervical (CI— 2) and high lumbar puncture. 
The risk of cord puncture is greatest in patients with 
spinal stenosis, Chiari malformations, or conditions that 
reduce CSF volume. In these settings, a low-dose lum- 
bar injection followed by thin-section CT or MRI is a 
safer alternative to cervical puncture. Intrathecal contrast 
reactions are rare, but aseptic meningitis and encephalopa- 
thy may occur. The latter is usually dose-related and 
associated with contrast entering the intracranial sub- 



arachnoid space. Seizures occur following myelography 
in 0.1—0.3% of patients. Risk factors include a preexist- 
ing seizure disorder and the use of a total iodine dose of 
>4500 mg. Other reported complications include 
hyperthermia, hallucinations, depression, and anxiety 
states. These side effects have been reduced by the devel- 
opment of nonionic, water-soluble contrast agents, as 
well as by head elevation and generous hydration fol- 
lowing myelography. 



SPINE INTERVENTIONS 

DISCOGRAPHY 

The evaluation of back pain and radiculopathy may require 
diagnostic procedures that attempt either to reproduce 
the patient's pain or relieve it, indicating its correct 
source prior to lumbar fusion. Discography is performed 
by fluoroscopic placement of a 22- to 25-gauge needle 
into the intervertebral disc and subsequent injection of 
1—3 mL of contrast media. The intradiscal pressure is 
recorded, as is an assessment of the patient's response to 
the injection of contrast material. Typically little or no 
pain is felt during injection of a normal disc, which does 
not accept much more than 1 mL of contrast material, 
even at pressures as high as 415—690 kPa (60—100 
lbs/in 2 ). CT and plain films are obtained following the 
procedure. 



SELECTIVE NERVE ROOT AND EPIDURAL 
SPINAL INJECTIONS 

Percutaneous selective nerve root and epidural blocks 
with glucocorticoid and anesthetic mixtures may be 
both therapeutic and diagnostic, especially if a patient's 
pain is relieved. Typically, 1—2 mL of an equal mixture 
of a long-acting glucocorticoid such as betamethasone 
and a long-acting anesthetic such as bupivicain 0.75% is 
instilled under CT or fluoroscopic guidance in the 
intraspinal epidural space or adjacent to an existing nerve 
root. 



ANGIOGRAPHY 

Catheter angiography is indicated for evaluating 
intracranial small-vessel pathology (such as vasculitis), for 
assessing vascular malformations and aneurysms, and in 
endovascular therapeutic procedures (Table 2-1). Angiog- 
raphy has been replaced for many indications by CT/CTA 
or MRI/MRA. 

Angiography carries the greatest risk of morbidity of 
all diagnostic imaging procedures, owing to the necessity 
of inserting a catheter into a blood vessel, directing the 
catheter to the required location, injecting contrast material 



to visualize the vessel, and removing the catheter while 
maintaining hemostasis. Therapeutic transcatheter proce- 
dures (see below) have become important options for the 
treatment of some cerebrovascular diseases. The decision 
to undertake a diagnostic or therapeutic angiographic 
procedure requires careful assessment of the goals of the 
investigation and its attendant risks. 

To improve tolerance to contrast agents, patients 
undergoing angiography should be well hydrated before 
and after the procedure. Since the femoral route is used 
most commonly, the femoral artery must be compressed 
after the procedure to prevent a hematoma from devel- 
oping. The puncture site and distal pulses should be 
evaluated carefully after the procedure; complications 
can include thigh hematoma or lower extremity emboli. 

COMPLICATIONS 

A common femoral arterial puncture provides retro- 
grade access via the aorta to the aortic arch and great 
vessels. The most feared complication of cerebral 
angiography is stroke. Thrombus can form on or inside 
the tip of the catheter, and atherosclerotic thrombus or 
plaque can be dislodged by the catheter or guide wire or 
by the force of injection and can embolize distally in the 
cerebral circulation. Risk factors for ischemic complica- 
tions include limited experience on the part of the 
angiographer, atherosclerosis, vasospasm, low cardiac 
output, decreased oxygen-carrying capacity, advanced 
age, and prior history of migraine. The risk of a neuro- 
logic complication varies but is ~4% for transient 
ischemic attack and stroke, 1% for permanent deficit, 
and <0.1% for death. 

Ionic contrast material injected into the cerebral vas- 
culature can be neurotoxic if the BBB is breached, 
either by an underlying disease or by the injection of 
hyperosmolar contrast agent. Ionic contrast media are 
less well tolerated than nonionic media, probably 
because they can induce changes in cell membrane elec- 
trical potentials. Patients with dolichoectasia of the basi- 
lar artery can suffer reversible brainstem dysfunction and 
acute short-term memory loss during angiography, 
owing to the slow percolation of the contrast material 
and the consequent prolonged exposure of the brain. 
Rarely, an intracranial aneurysm ruptures during an 
angiographic contrast injection, causing subarachnoid 
hemorrhage, perhaps as a result of injection under high 
pressure. 



SPINAL ANGIOGRAPHY 

Spinal angiography may be indicated to evaluate vascular 
malformations and tumors and to identify the artery of 
Adamkiewicz (Chap. 30) prior to aortic aneurysm repair. 
The procedure is lengthy and requires the use of relatively 
large volumes of contrast; the incidence of serious com- 
plications, including paraparesis, subjective visual blurring, 
and altered speech, is ~2%. Gadolinium-enhanced MRA 
has been used successfully in this setting, as has iodinated 
contrast CTA, which has promise for replacing diagnostic 
spinal angiography for some indications. 

INTERVENTIONAL NEURORADIOLOGY 

This rapidly developing field is providing new therapeu- 
tic options for patients with challenging neurovascular 
problems. Available procedures include detachable coil 
therapy for aneurysms, particulate or liquid adhesive 
embolization of arteriovenous malformations, balloon 
angioplasty and stenting of arterial stenosis or vasospasm, 
transarterial or transvenous embolization of dural arteri- 
ovenous fistulas, balloon occlusion of carotid-cavernous 
and vertebral fistulas, endovascular treatment of vein- 
of-Galen malformations, preoperative embolization of 
tumors, and thrombolysis of acute arterial or venous 
thrombosis. Many of these disorders place the patient at 
high risk of cerebral hemorrhage, stroke, or death. 

The highest complication rates are found with the 
therapies designed to treat the highest-risk diseases. The 
advent of electrolytically detachable coils has ushered in 
a new era in the treatment of cerebral aneurysms. One 
randomized trial found a 28% reduction of morbidity 
and mortality at 1 year among those treated for anterior 
circulation aneurysm with detachable coils compared 
with neurosurgical clipping. It remains to be determined 
what the role of coils 'will be relative to surgical options, 
but in many centers, coiling has become standard ther- 
apy for many aneurysms. 

FURTHER READINGS 

DONNAN GA et al: Penumbral selection of patients for trials of acute 
stroke therapy. Lancet Neurol. 8:261, 2009 

ROVARIS M et al: Diffusion tensor MR imaging. Neuroimaging Clin 
NArn 19:37,2009 

SCHAEFER PW: Diffusion-weighted imaging in acute stroke. Magn 
Reson Imaging Clin N Am 14:141, 2006 

VERNOOIJ MW et al: Incidental findings on brain MRI in the gen- 
eral population. N EnglJ Med 357:1821, 2007 



23 



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CHAPTER 3 

ELECTRODIAGNOSTIC STUDIES OF NERVOUS 

SYSTEM DISORDERS: EEG, EVOKED 

POTENTIALS, AND EMG 



Michael J. Aminoff 



Electroencephalography 24 

The EEG and Epilepsy 24 

The EEG and Coma 26 

The EEG in Other Neurologic Disorders 27 

Evoked Potentials 27 

Sensory Evoked Potentials 27 

Clinical Utility of SEPs 27 

Electrophysiologic Studies of Muscle and Nerve 28 

Electromyography 28 

Further Readings 32 



ELECTROENCEPHALOGRAPHY 

The electrical activity of the brain [the electroencephalo- 
gram (EEG)] is easily recorded from electrodes placed on 
the scalp. The potential difference between pairs of elec- 
trodes on the scalp (bipolar derivation) or between indi- 
vidual scalp electrodes and a relatively inactive common 
reference point (referential derivation) is amplified and 
displayed on a computer monitor, oscilloscope, or paper. 
The characteristics of the normal EEG depend on the 
patient's age and level of arousal. The rhythmic activity 
normally recorded represents the postsynaptic potentials 
of vertically oriented pyramidal cells of the cerebral cor- 
tex and is characterized by its frequency. In normal 
awake adults lying quietly with the eyes closed, an 8- to 
13-Hz alpha rhythm is seen posteriorly in the EEG, 
intermixed with a variable amount of generalized faster 
(beta) activity (>13 Hz); the alpha rhythm is attenuated 
when the eyes are opened (Fig. 3-1). During drowsiness, 
the alpha rhythm is also attenuated; with light sleep, 
slower activity in the theta (4-7 Hz) and delta (<4 Hz) 
ranges becomes more conspicuous. 

The EEG is best recorded from several different elec- 
trode arrangements (montages) in turn, and activating 



procedures are generally undertaken in an attempt to 
provoke abnormalities. Such procedures commonly 
include hyperventilation (for 3 or 4 min), photic stimu- 
lation, sleep, and sleep deprivation on the night prior to 
the recording. 

Electroencephalography is relatively inexpensive and 
may aid clinical management in several different contexts. 



THE EEG AND EPILEPSY 

The EEG is most useful in evaluating patients with sus- 
pected epilepsy. The presence of electrographic seizure 
activity — i.e., of abnormal, repetitive, rhythmic activity 
having an abrupt onset and termination and a character- 
istic evolution — clearly establishes the diagnosis. The 
absence of such electrocerebral accompaniment does 
not exclude a seizure disorder, however, because there 
may be no change in the scalp-recorded EEG during 
simple or complex partial seizures. With generalized 
tonic-clonic seizures, however, the EEG is always abnor- 
mal during the episode. It is often not possible to obtain 
an EEG during clinical events that may represent seizures, 
especially when such events occur unpredictably or infre- 
quently. Continuous monitoring for prolonged periods 



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FIGURE 3-1 

A Normal EEG showing a posteriorly situated 9-Hz alpha 
rhythm that attenuates with eye opening. B. Abnormal EEG 
showing irregular diffuse slow activity in an obtunded patient 
with encephalitis. C. Irregular slow activity in the right central 
region, on a diffusely slowed background, in a patient with a 
right parietal glioma. D. Periodic complexes occurring once 
every second in a patient with Creutzfeldt-Jakob disease. 
Horizontal calibration: 1 s; vertical calibration: 200 ^V in A, 



in video-EEG telemetry units for hospitalized patients 
or the use of portable equipment to record the EEG 
continuously on cassettes for 24 h or longer in ambula- 
tory patients has made it easier to capture the electro- 
cerebral accompaniments of such clinical episodes. 
Monitoring by these means is sometimes helpful in con- 
firming that seizures are occurring, characterizing the 
nature of clinically equivocal episodes, and determining 
the frequency of epileptic events. 

The EEG findings may also be helpful in the interictal 
period by showing certain abnormalities that are strongly 
supportive of a diagnosis of epilepsy. Such epileptiform 
activity consists of bursts of abnormal discharges contain- 
ing spikes or sharp waves. The presence of epileptiform 
activity is not specific for epilepsy, but it has a much 
greater prevalence in epileptic patients than in normal 
individuals. However, even in an individual who is 
known to have epilepsy, the initial routine interictal EEG 
may be normal up to 60% of the time. Thus, the EEG 
cannot establish the diagnosis of epilepsy in many cases. 

The EEG findings have been used in classifying 
seizure disorders and selecting appropriate anticonvul- 
sant medication for individual patients (Fig. 3-2). The 



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300 |iV in other panels. (From Aminoff, 1999.) In this and the 
following figure, electrode placements are indicated at the 
left of each panel and accord with the international 10:20 
system. A, earlobe; C, central; F, frontal; Fp, frontal polar; 
P, parietal; T, temporal; O, occipital. Right-sided placements 
are indicated by even numbers, left-sided placements by 
odd numbers, and midline placements by Z. 



episodic generalized spike-wave activity that occurs dur- 
ing and between seizures in patients with typical 
absence epilepsy contrasts with focal interictal epilepti- 
form discharges or ictal patterns found in patients with 
complex partial seizures. These latter seizures may have 
no correlates in the scalp-recorded EEG or may be asso- 
ciated with abnormal rhythmic activity of variable fre- 
quency, a localized or generalized distribution, and a 
stereotyped pattern that varies with the patient. Focal or 
lateralized epileptogenic lesions are important to recog- 
nize, especially if surgical treatment is contemplated. 
Intensive long-term monitoring of clinical behavior and 
the EEG is required for operative candidates, however, 
and this generally also involves recording from intracra- 
nialfy placed electrodes (which may be subdural, 
extradural, or intracerebral in location) . 

The findings in the routine scalp-recorded EEG may 
indicate the prognosis of seizure disorders: in general, a 
normal EEG implies a better prognosis than otherwise, 
whereas an abnormal background or profuse epilepti- 
form activity suggests a poor outlook. The EEG findings 
are not helpful in determining which patients with head 
injuries, stroke, or brain tumors will go on to develop 



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occur after withdrawal of anticonvulsant medication 
despite a normal EEG or, conversely, may not occur 
despite a continuing EEG abnormality. The decision to 
discontinue anticonvulsant medication is made on clini- 
cal grounds, and the EEG does not have a useful role in 
this context except for providing guidance when there 
is clinical ambiguity or the patient requires reassurance 
about a particular course of action. 

The EEG has no role in the management of tonic- 
clonic status epilepticus except when there is clinical 
uncertainty whether seizures are continuing in a 
comatose patient. In patients treated by pentobarbital- 
induced coma for refractory status epilepticus, the EEG 
findings are useful in indicating the level of anesthesia 
and whether seizures are occurring. During status 
epilepticus, the EEG shows repeated electrographic 
seizures or continuous spike-wave discharges. In non- 
convulsive status epilepticus, a disorder that may not be 
recognized unless an EEG is performed, the EEG may 
also show continuous spike-wave activity ("spike -wave 
stupor") or, less commonly, repetitive electrographic 
seizures (complex partial status epilepticus) . 



Fp1-A1 

F7-A1 
T3-A1 
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FIGURE 3-2 

Electrographic seizures. A. Onset of a tonic seizure showing 
generalized repetitive sharp activity with synchronous onset 
over both hemispheres. B. Burst of repetitive spikes occur- 
ring with sudden onset in the right temporal region during a 
clinical spell characterized by transient impairment of external 
awareness. C. Generalized 3-Hz spike-wave activity occur- 
ring synchronously over both hemispheres during an absence 
(petit mal) attack. Horizontal calibration: 1 s; vertical calibra- 
tion: 400 mV in A, 200 mV in B, and 750 mV in C. {From 
Aminoff, 1999.) 



seizures, because in such circumstances epileptiform 
activity is commonly encountered regardless of whether 
seizures occur. The EEG findings are sometimes used to 
determine whether anticonvulsant medication can be 
discontinued in epileptic patients who have been 
seizure-free for several years, but the findings provide 
only a general guide to prognosis: further seizures may 



THE EEG AND COMA 

In patients with an altered mental state or some degree of 
obtundation, the EEG tends to become slower as con- 
sciousness is depressed, regardless of the underlying cause 
(Fig. 3-1). Other findings may also be present and may 
suggest diagnostic possibilities, as when electrographic 
seizures are found or there is a focal abnormality indicat- 
ing a structural lesion. The EEG generally slows in meta- 
bolic encephalopathies, and triphasic waves may be pre- 
sent. The findings do not permit differentiation of the 
underlying metabolic disturbance but help to exclude 
other encephalopathic processes by indicating the diffuse 
extent of cerebral dysfunction. The response of the EEG 
to external stimulation is helpful prognosticaUy because 
electrocerebral responsiveness implies a lighter level of 
coma than a nonreactive EEG. Serial records provide a 
better guide to prognosis than a single record and supple- 
ment the clinical examination in following the course of 
events. As the depth of coma increases, the EEG becomes 
nonreactive and may show a burst-suppression pattern, 
with bursts of mixed-frequency activity separated by 
intervals of relative cerebral inactivity. In other instances 
there is a reduction in amplitude of the EEG until even- 
tually activity cannot be detected. Such electrocerebral 
silence does not necessarily reflect irreversible brain dam- 
age, because it may occur in hypothermic patients or with 
drug overdose. The prognosis of electrocerebral silence, 
when recorded using an adequate technique, depends 
upon the clinical context in which it is found. In patients 
with severe cerebral anoxia, for example, electrocerebral 
silence in a technically satisfactory record implies that 
useful cognitive recovery will not occur. 



In patients with clinically suspected brain death, an 
EEG, when recorded using appropriate technical stan- 
dards, may be confirmatory by showing electrocerebral 
silence. However, complicating disorders that may pro- 
duce a similar but reversible EEG appearance (e.g., 
hypothermia or drug intoxication) must be excluded. 
The presence of residual EEG activity in suspected brain 
death fails to confirm the diagnosis but does not exclude 
it. The EEG is usually normal in patients with locked-in 
syndrome and helps in distinguishing this disorder from 
the comatose state with which it is sometimes confused 
clinically. 

THE EEG IN OTHER NEUROLOGIC 
DISORDERS 

In the developed countries, CT scanning and MRI have 
taken the place of EEG as a noninvasive means of screen- 
ing for focal structural abnormalities of the brain, such as 
tumors, infarcts, or hematomas (Fig. 3-1). Nonetheless, 
the EEG is still used for this purpose in many parts of the 
world, although infratentorial or slowly expanding 
lesions may fail to cause any abnormalities. Focal slow- 
wave disturbances, a localized loss of electrocerebral 
activity, or more generalized electrocerebral disturbances 
are common findings but provide no reliable indication 
about the nature of the underlying pathology. 

In patients with an acute encephalopathy, focal or lat- 
eralized periodic slow-wave complexes, sometimes with 
a sharpened outline, suggest a diagnosis of herpes sim- 
plex encephalitis, and periodic lateralized epileptiform 
discharges (PLEDs) are commonly found with acute 
hemispheric pathology such as a hematoma, abscess, or 
rapidly expanding tumor. The EEG findings in dementia 
are usually nonspecific and do not distinguish between 
the different causes of cognitive decline except in rare 
instances when, for example, the presence of complexes 
occurring with a regular repetition rate (so-called peri- 
odic complexes) supports a diagnosis of Creutzfeldt- 
Jakob disease (Fig. 3-1) or subacute sclerosing panen- 
cephalitis. In most patients with dementias, the EEG is 
normal or diffusely slowed, and the EEG findings alone 
cannot indicate whether a patient is demented or distin- 
guish between dementia and pseudodementia. 

EVOKED POTENTIALS 

SENSORY EVOKED POTENTIALS 

The noninvasive recording of spinal or cerebral poten- 
tials elicited by stimulation of specific afferent pathways 
is an important means of monitoring the functional 
integrity of these pathways but does not indicate the 
pathologic basis of lesions involving them. Such evoked 
potentials (EPs) are so small compared to the back- 
ground EEG activity that the responses to a number of 



stimuli have to be recorded and averaged with a com- 
puter in order to permit their recognition and defini- 
tion. The background EEG activity, which has no fixed 
temporal relationship to the stimulus, is averaged out by 
this procedure. 

Visual evoked potentials (VEPs) are elicited by monocular 
stimulation with a reversing checkerboard pattern and are 
recorded from the occipital region in the midline and on 
either side of the scalp. The component of major clinical 
importance is the so-called PI 00 response, a positive peak 
having a latency of approximately 100 ms. Its presence, 
latency, and symmetry over the two sides of the scalp are 
noted. Amplitude may also be measured, but changes in 
size are much less helpful for the recognition of pathology. 
VEPs are most useful in detecting dysfunction of the 
visual pathways anterior to the optic chiasm. In patients 
with acute severe optic neuritis, the PI 00 is frequently lost 
or grossly attenuated; as clinical recovery occurs and visual 
acuity improves, the P100 is restored but with an increased 
latency that generally remains abnormally prolonged 
indefinitely. The VEP findings are therefore helpful in indi- 
cating previous or subclinical optic neuritis. They may also 
be abnormal with ocular abnormalities and with other 
causes of optic nerve disease, such as ischemia or compres- 
sion by a tumor. Normal VEPs may be elicited by flash 
stimuli in patients with cortical blindness. 

Brainstem auditory evoked potentials (BAEPs) are elicited 
by monaural stimulation with repetitive clicks and are 
recorded between the vertex of the scalp and the mas- 
toid process or earlobe. A series of potentials, designated 
by roman numerals, occurs in the first 10 ms after the 
stimulus and represents in part the sequential activation 
of different structures in the pathway between the audi- 
tory nerve (wave I) and the inferior colliculus (waveV) 
in the midbrain. The presence, latency, and interpeak 
latency of the first five positive potentials recorded at 
the vertex are evaluated. The findings are helpful in 
screening for acoustic neuromas, detecting brainstem 
pathology, and evaluating comatose patients. The BAEPs 
are normal in coma due to metabolic/toxic disorders or 
bihemispheric disease but abnormal in the presence of 
brainstem pathology. 

Somatosensory evoked potentials (SEPs) are recorded 
over the scalp and spine in response to electrical stimu- 
lation of a peripheral (mixed or cutaneous) nerve. The 
configuration, polarity, and latency of the responses 
depend on the nerve that is stimulated and on the record- 
ing arrangements. SEPs are used to evaluate proximal 
(otherwise inaccessible) portions of the peripheral nervous 
system and the integrity of the central somatosensory 
pathways. 

CLINICAL UTILITY OF SEPs 

EP studies may detect and localize lesions in afferent 
pathways in the central nervous system (CNS). They 



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have been used particularly to investigate patients with 
suspected multiple sclerosis (MS), the diagnosis of which 
requires the recognition of lesions involving several dif- 
ferent regions of the central white matter. In patients 
with clinical evidence of only one lesion, the electro- 
physiologic recognition of abnormalities in other sites 
helps to suggest or support the diagnosis but does not 
establish it unequivocally. Multimodality EP abnormali- 
ties are not specific for multiple sclerosis (MS); they may 
occur in AIDS, Lyme disease, systemic lupus erythe- 
matosus, neurosyphilis, spinocerebellar degenerations, 
familial spastic paraplegia, and deficiency of vitamin E 
or B 12 , among other disorders. The diagnostic utility of 
the electrophysiologic findings therefore depends on the 
circumstances in which they are found. Abnormalities 
may aid in the localization of lesions to broad areas of 
the CNS, but attempts at precise localization on electro- 
physiologic grounds are misleading because the genera- 
tors of many components of the EP are unknown. 

The EP findings are sometimes of prognostic rele- 
vance. Bilateral loss of SEP components that are gener- 
ated in the cerebral cortex implies that cognition may 
not be regained in posttraumatic or postanoxic coma, 
and EP studies may also be useful in evaluating patients 
with suspected brain death. In patients who are comatose 
for uncertain reasons, preserved BAEPs suggest either a 
metabolic-toxic etiology or bihemispheric disease. In 
patients with spinal cord injuries, SEPs have been used to 
indicate the completeness of the lesion. The presence or 
early return of a cortically generated response to stimula- 
tion of a nerve below the injured segment of the cord 
indicates an incomplete lesion and thus a better progno- 
sis for functional recovery than otherwise. In surgery, 
intraoperative EP monitoring of neural structures placed 
at risk by the procedure may permit the early recogni- 
tion of dysfunction and thereby permit a neurologic 
complication to be averted or minimized. 

Visual and auditory acuity may be determined using EP 
techniques in patients whose age or mental state precludes 
traditional ophthalmologic or audiologic examinations. 

Cognitive Evoked Potentials 

Certain EP components depend on the mental attention 
of the subject and the setting in which the stimulus occurs, 
rather than simply on the physical characteristics of the 
stimulus. Such "event-related" potentials (ERPs) or 
"endogenous" potentials are related in some manner to 
the cognitive aspects of distinguishing an infrequently 
occurring target stimulus from other stimuli occurring 
more frequently. For clinical purposes, attention has 
been directed particularly at the so-called P3 compo- 
nent of the ERP which is also designated the P300 
component because of its positive polarity and latency 
of approximately 300—400 ms after onset of an auditory 
target stimulus. The P3 component is prolonged in 



latency in many patients with dementia, whereas it is 
generally normal in patients with depression or other 
psychiatric disorders that might be mistaken for demen- 
tia. ERPs are therefore sometimes helpful in making this 
distinction when there is clinical uncertainty, although a 
response of normal latency does not exclude dementia. 

Motor Evoked Potentials 

The electrical potentials recorded from muscle or the 
spinal cord following stimulation of the motor cortex or 
central motor pathways are referred to as motor evoked 
potentials. For clinical purposes such responses are 
recorded most often as the compound muscle action 
potentials elicited by transcutaneous magnetic stimula- 
tion of the motor cortex. A strong but brief magnetic 
field is produced by passing a current through a coil, and 
this induces stimulating currents in the subjacent neural 
tissue. The procedure is painless and apparently safe. 
Abnormalities have been described in several neurologic 
disorders with clinical or subclinical involvement of 
central motor pathways, including MS and motor neu- 
ron disease. In addition to a possible role in the diagnosis 
of neurologic disorders or in evaluating the extent of 
pathologic involvement, the technique provides infor- 
mation of prognostic relevance (e.g., in suggesting the 
likelihood of recovery of motor function after stroke) 
and is useful as a means of monitoring intraoperatively 
the functional integrity of central motor tracts. 

ELECTROPHYSIOLOGIC STUDIES 
OF MUSCLE AND NERVE 

The motor unit is the basic element subserving motor 
function. It is defined as an anterior horn cell, its axon 
and neuromuscular junctions, and all the muscle fibers 
innervated by the axon. The number of motor units in a 
muscle ranges from approximately 10 in the extraocular 
muscles to several thousand in the large muscles of the 
legs. There is considerable variation in the average num- 
ber of muscle fibers within the motor units of an indi- 
vidual muscle, i.e., in the innervation ratio of different 
muscles. Thus the innervation ratio is <25 in the human 
external rectus or platysma muscle and between 1600 
and 1700 in the medial head of the gastrocnemius mus- 
cle. The muscle fibers of individual motor units are 
divided into two general types by distinctive contractile 
properties, histochemical stains, and characteristic 
responses to fatigue. Within each motor unit, all of the 
muscle fibers are of the same type. 



ELECTROMYOGRAPHY 

The pattern of electrical activity in muscle [i.e., the 
electromyogram (EMG)], both at rest and during activ- 
ity, may be recorded from a needle electrode inserted 




100|jV 



10 ms 



^a^^f^^ ]ioonv 



100 ms 



1 



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10 ms 



FIGURE 3-3 

Activity recorded during EMG. A. Spontaneous fibrillation 
potentials and positive sharp waves. B. Complex repetitive 
discharges recorded in partially denervated muscle at rest. 
C. Normal triphasic motor unit action potential. D. Small, 
short-duration, polyphasic motor unit action potential such 
as is commonly encountered in myopathic disorders. E. Long- 
duration polyphasic motor unit action potential such as may 
be seen in neuropathic disorders. 



into the muscle. The nature and pattern of abnormalities 
relate to disorders at different levels of the motor unit. 

Relaxed muscle normally is electrically silent except 
in the end plate region, but abnormal spontaneous 
activity (Fig. 3-3) occurs in various neuromuscular dis- 
orders, especially those associated with denervation or 
inflammatory changes in affected muscle. Fibrillation 
potentials and positive sharp waves (which reflect mus- 
cle fiber irritability) and complex repetitive discharges 
are most often — but not always — found in denervated 
muscle and may also occur after muscle injury and in 
certain myopathic disorders, especially inflammatory dis- 
orders such as polymyositis. After an acute neuropathic 
lesion, they are found earlier in proximal rather than dis- 
tal muscles and sometimes do not develop distally in the 
extremities for 4—6 weeks; once present, they may persist 
indefinitely unless reinnervation occurs or the muscle 
degenerates so completely that no viable tissue remains. 
Fasciculation potentials (which reflect the spontaneous 
activity of individual motor units) are characteristic of 
slowly progressive neuropathic disorders, especially those 
with degeneration of anterior horn cells (such as amy- 
otrophic lateral sclerosis). Myotonic discharges — high- 
frequency discharges of potentials derived from single 
muscle fibers that wax and wane in amplitude and 
frequency — are the signature of myotonic disorders such 
as myotonic dystrophy or myotonia congenita but occur 
occasionally in polymyositis or other, rarer, disorders. 

Slight voluntary contraction of a muscle leads to acti- 
vation of a small number of motor units. The potentials 
generated by any muscle fibers of these units that are 
within the pick-up range of the needle electrode will be 



recorded (Fig. 3-3). The parameters of normal motor 
unit action potentials depend on the muscle under study 
and age of the patient, but their duration is normally 
between 5 and 15 ms, amplitude is between 200 |J,V and 
2 mV, and most are bi- or triphasic. The number of units 
activated depends on the degree of voluntary activity. An 
increase in muscle contraction is associated with an 
increase in the number of motor units that are activated 
(recruited) and in the frequency with which they dis- 
charge. With a full contraction, so many motor units are 
normally activated that individual motor unit action 
potentials can no longer be distinguished, and a com- 
plete interference pattern is said to have been produced. 

The incidence of small, short-duration, polyphasic 
motor unit action potentials (i.e., having more than four 
phases) is usually increased in myopathic muscle, and an 
excessive number of units is activated for a specified 
degree of voluntary activity. By contrast, the loss of 
motor units that occurs in neuropathic disorders leads to 
a reduction in number of units activated during a maxi- 
mal contraction and an increase in their firing rate, i.e., 
there is an incomplete or reduced interference pattern. 
The configuration and dimensions of the potentials may 
also be abnormal, depending on the duration of the 
neuropathic process and on whether reinnervation has 
occurred. The surviving motor units are initially normal 
in configuration but, as reinnervation occurs, they 
increase in amplitude and duration and become 
polyphasic (Fig. 3-3). 

Action potentials from the same motor unit some- 
times fire with a consistent temporal relationship to each 
other, so that double, triple, or multiple discharges are 
recorded, especially in tetany, hemifacial spasm, or 
myokymia. 

Electrical silence characterizes the involuntary, sus- 
tained muscle contraction that occurs in phosphorylase 
deficiency, which is designated a contracture. 

EMG enables disorders of the motor units to be 
detected and characterized as either neurogenic or myo- 
pathic. In neurogenic disorders, the pattern of affected 
muscles may localize the lesion to the anterior horn 
cells or to a specific site as the axons traverse a nerve 
root, limb plexus, and peripheral nerve to their terminal 
arborizations. The findings do not enable a specific etio- 
logic diagnosis to be made, however, except in conjunc- 
tion with the clinical findings and results of other labo- 
ratory studies. 

The findings may provide a guide to the severity of 
an acute disorder of a peripheral or cranial nerve (by 
indicating whether denervation has occurred and the 
completeness of the lesion) and whether the pathologic 
process is active or progressive in chronic or degenera- 
tive disorders such as amyotrophic lateral sclerosis. Such 
information is important for prognostic purposes. 

Various quantitative EMG approaches have been 
developed. The most common is to determine the mean 



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duration and amplitude of 20 motor unit action poten- 
tials using a standardized technique. The technique of 
macro-EMG provides information about the number 
and size of muscle fibers in a larger volume of the motor 
unit territory and has also been used to estimate the 
number of motor units in a muscle. Scanning EMG is a 
computer-based technique that has been used to study 
the topography of motor unit action potentials and, in 
particular, the spatial and temporal distribution of activ- 
ity in individual units. The technique of single-fiber 
EMG is discussed separately later. 

Nerve Conduction Studies 

Recording of the electrical response of a muscle to 
stimulation of its motor nerve at two or more points 
along its course (Fig. 3-4) permits conduction velocity 
to be determined in the fastest-conducting motor fibers 
between the points of stimulation. The latency and ampli- 
tude of the electrical response of muscle (i.e., of the 
compound muscle action potential) to stimulation of its 
motor nerve at a distal site are also compared with values 
defined in normal subjects. Sensory nerve conduction 



Recording 
electrodes 

Reference- 
Active 
Cathode 
Anode 




Stimulating 
electrodes 



*L>* 



Stimulating 
electrodes 



Stimulation 
site 

Wrist 



Below 
elbow 



Above 
elbow 



Axilla 




5mV 



10 ms 



FIGURE 3-4 

Arrangement for motor conduction studies of the ulnar nerve. 
Responses are recorded with a surface electrode from the 
abductor digiti minimi muscle to supramaximal stimulation of 
the nerve at different sites, and are shown in the lower panel. 
(From Aminoff, 1998.) 



studies are performed by determining the conduction 
velocity and amplitude of action potentials in sensory 
fibers when these fibers are stimulated at one point and 
the responses are recorded at another point along the 
course of the nerve. In adults, conduction velocity in the 
arms is normally between 50 and 70 m/s, and in the legs 
is between 40 and 60 m/s. 

Nerve conduction studies complement the EMG 
examination, enabling the presence and extent of 
peripheral nerve pathology to be determined. They are 
particularly helpful in determining whether sensory 
symptoms are arising from pathology proximal or distal 
to the dorsal root ganglia (in the former instance, 
peripheral sensory conduction studies will be normal) 
and whether neuromuscular dysfunction relates to 
peripheral nerve disease. In patients with a mononeu- 
ropathy, they are invaluable as a means of localizing a 
focal lesion, determining the extent and severity of the 
underlying pathology, providing a guide to prognosis, 
and detecting subclinical involvement of other periph- 
eral nerves. They enable a polyneuropathy to be distin- 
guished from a mononeuropathy multiplex when this is 
not possible clinically, an important distinction because 
of the etiologic implications. Nerve conduction studies 
provide a means of following the progression and thera- 
peutic response of peripheral nerve disorders and are 
being used increasingly for this purpose in clinical trials. 
They may suggest the underlying pathologic basis in 
individual cases. Conduction velocity is often markedly 
slowed, terminal motor latencies are prolonged, and 
compound motor and sensory nerve action potentials 
may be dispersed in the demyelinative neuropathies 
(such as in Guillain-Barre syndrome, chronic inflamma- 
tory polyneuropathy, metachromatic leukodystrophy, or 
certain hereditary neuropathies); conduction block is 
frequent in acquired varieties of these neuropathies. By 
contrast, conduction velocity is normal or slowed only 
mildly, sensory nerve action potentials are small or 
absent, and there is EMG evidence of denervation in 
axonal neuropathies such as occur in association with 
metabolic or toxic disorders. 

The utility and complementary role of EMG and 
nerve conduction studies are best illustrated by reference 
to a common clinical problem. Numbness and paresthe- 
sia of the little finger and associated wasting of the 
intrinsic muscles of the hand may result from a spinal 
cord lesion, C8/T1 radiculopathy, brachial plexopathy 
(lower trunk or medial cord), or a lesion of the ulnar 
nerve. If sensory nerve action potentials can be recorded 
normally at the wrist following stimulation of the digital 
fibers in the affected finger, the pathology is probably 
proximal to the dorsal root ganglia, i.e., there is a radicu- 
lopathy or more central lesion; absence of the sensory 
potentials, by contrast, suggests distal pathology. EMG 
examination will indicate whether the pattern of 
affected muscles conforms to radicular or ulnar nerve 



territory, or is more extensive (thereby favoring a plex- 
opathy). Ulnar motor conduction studies will generally 
also distinguish between a radiculopathy (normal find- 
ings) and ulnar neuropathy (abnormal findings) and will 
often identify the site of an ulnar nerve lesion: the nerve 
is stimulated at several points along its course to deter- 
mine whether the compound action potential recorded 
from a distal muscle that it supplies shows a marked 
alteration in size or area or a disproportionate change in 
latency, with stimulation at a particular site. The electro- 
physiologic findings thus permit a definitive diagnosis to 
be made and specific treatment instituted in circum- 
stances where there is clinical ambiguity. 

F Wave Studies 

Stimulation of a motor nerve causes impulses to travel 
antidromically (i.e., toward the spinal cord) as well as 
orthodromically (to the nerve terminals). Such antidromic 
impulses cause a few of the anterior horn cells to dis- 
charge, producing a small motor response that occurs 
considerably later than the direct response elicited by nerve 
stimulation. The F wave so elicited is sometimes abnormal 
(absent or delayed) with proximal pathology of the periph- 
eral nervous system, such as a radiculopathy, and may 
therefore be helpful in detecting abnormalities when 
conventional nerve conduction studies are normal. In 
general, however, the clinical utility of F wave studies has 
been disappointing, except perhaps in Guillain-Barre 
syndrome, where they are often absent or delayed. 

H Reflex Studies 

The H reflex is easily recorded only from the soleus mus- 
cle (SI) in normal adults. It is elicited by low-intensity 
stimulation of the tibial nerve and represents a monosy- 
naptic reflex in which spindle (la) afferent fibers consti- 
tute the afferent arc and alpha motor axons the efferent 
pathway. The H reflexes are often absent bilaterally in 
elderly patients or with polyneuropathies and may be 
lost unilaterally in SI radiculopathies. 

Muscle Response to Repetitive 
Nerve Stimulation 

The size of the electrical response of a muscle to supra- 
maximal electrical stimulation of its motor nerve relates 
to the number of muscle fibers that are activated. Neu- 
romuscular transmission can be tested by several differ- 
ent protocols, but the most helpful is to record with sur- 
face electrodes the electrical response of a muscle to 
supramaximal stimulation of its motor nerve by repeti- 
tive (2—3 Hz) shocks delivered before and at selected 
intervals after a maximal voluntary contraction. 

There is normally little or no change in size of the 
compound muscle action potential following repetitive 



stimulation of a motor nerve at 2—3 Hz with stimuli 
delivered at intervals after voluntary contraction of the 
muscle for about 20—30 s, even though preceding activ- 
ity in the junctional region influences the release of 
acetylcholine and thus the size of the end plate poten- 
tials elicited by a test stimulus. This is because more 
acetylcholine is normally released than is required to 
bring the motor end plate potentials to the threshold for 
generating muscle fiber action potentials. In disorders of 
neuromuscular transmission this safety factor is reduced. 
Thus in myasthenia gravis, repetitive stimulation, partic- 
ularly at a rate of between 2 and 5 Hz, may lead to a 
depression of neuromuscular transmission, with a decre- 
ment in size of the response recorded from affected 
muscles. Similarly, immediately after a period of maxi- 
mal voluntary activity, single or repetitive stimuli of the 
motor nerve may elicit larger muscle responses than 
before, indicating that more muscle fibers are respond- 
ing. This postactivation facilitation of neuromuscular 
transmission is followed by a longer-lasting period of 
depression, maximal between 2 and 4 min after the con- 
ditioning period and lasting for as long as 10 min or so, 
during which responses are reduced in size. 

Decrementing responses to repetitive stimulation at 
2—5 Hz are common in myasthenia gravis but may also 
occur in the congenital myasthenic syndromes. In 
Lambert-Eaton myasthenic syndrome, in which there is 
defective release of acetylcholine at the neuromuscular 
junction, the compound muscle action potential elicited 
by a single stimulus is generally very small. With repeti- 
tive stimulation at rates of up to 10 Hz, the first few 
responses may decline in size, but subsequent responses 
increase. If faster rates of stimulation are used (20—50 Hz), 
the increment may be dramatic so that the amplitude of 
compound muscle action potentials eventually reaches a 
size that is several times larger than the initial response. 
In patients with botulism, the response to repetitive 
stimulation is similar to that in Lambert-Eaton syn- 
drome, although the findings are somewhat more vari- 
able and not all muscles are affected. 



Single-Fiber Electromyography 

This technique is particularly helpful in detecting disor- 
ders of neuromuscular transmission. A special needle 
electrode is placed within a muscle and positioned to 
record action potentials from two muscle fibers belong- 
ing to the same motor unit. The time interval between 
the two potentials will vary in consecutive discharges; 
this is called the neuromuscular jitter. The jitter can be 
quantified as the mean difference between consecutive 
interpotential intervals and is normally between 10 and 
50 |ls.This value is increased when neuromuscular trans- 
mission is disturbed for any reason, and in some 
instances impulses in individual muscle fibers may fail to 
occur because of impulse blocking at the neuromuscular 



31 



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32 junction. Single-fiber EMG is more sensitive than repet- 
itive nerve stimulation or determination of acetylcholine 
receptor antibody levels in diagnosing myasthenia gravis. 
Single-fiber EMG can also be used to determine the 
mean fiber density of motor units (i.e., mean number of 
muscle fibers per motor unit within the recording area) 
and to estimate the number of motor units in a muscle, 
but this is of less immediate clinical relevance. 

= Blink Reflexes 

o 

^- Electrical or mechanical stimulation of the supraorbital 

nerve on one side leads to two separate reflex responses 
of the orbicularis oculi — an ipsilateral Rl response hav- 
ing a latency of approximately 10 ms and a bilateral R2 
response with a latency in the order of 30 ms. The 
trigeminal and facial nerves constitute the afferent and 
efferent arcs of the reflex, respectively. Abnormalities of 
either nerve or intrinsic lesions of the medulla or pons 



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may lead to uni- or bilateral loss of the response, and the 
findings may therefore be helpful in identifying or local- 
izing such pathology. 

FURTHER READINGS 

AMINOFF MJ: Electromyography in Clinical Practice: Electrodiagnostic 
Aspects of Neuromuscular Disease, 3d ed. New York, Churchill 
Livingstone, 1998 

( c d): Electrodiagnosis in Clinical Neurology, 5th ed. New York, 

Churchill Livingstone, 2005 

BROWN WF et al (eds): Neuromuscular Function and Disease. Philadel- 
phia, Saunders, 2002 

Ebersole JS, Pedley TA (eds): Current Practice of Clinical Electroen- 
cephalography, 3d ed. Philadelphia, Lippincott Williams & Wilkins, 
2003 

HOLMES GL et al: Clinical Neurophysiology of Infancy, Childhood, and 
Adolescence. Philadelphia, Butterworth Heinemann, 2006 

KlMURA J: Electrodiagnosis in Diseases of Nerve and Muscle, 3d ed. New 
York, Oxford University Press, 2001 




Elizabeth Robbins ■ Stephen L. Hauser 



Imaging and Laboratory Studies Prior to LP 33 

Analgesia 33 

Positioning 34 

Technique 34 

Post-LP Headache 35 

Normal Values 36 

Further Readings 36 



In experienced hands, lumbar puncture (LP) is usually a 
safe procedure. Major complications are extremely 
uncommon but can include cerebral herniation, injury 
to the spinal cord or nerve roots, hemorrhage, or infec- 
tion. Minor complications occur with greater frequency 
and can include backache, post-LP headache, and radic- 
ular pain or numbness. 

IMAGING AND LABORATORY STUDIES 
PRIOR TO LP 

Patients with an altered level of consciousness, a focal 
neurologic deficit, new-onset seizure, papilledema, or an 
immunocompromised state are at increased risk for 
potentially fatal cerebellar or tentorial herniation fol- 
lowing LP. Neuroimaging should be obtained in these 
patients prior to LP to exclude a focal mass lesion or 
diffuse swelling. Imaging studies should include the spine 
in patients with symptoms suggesting cord compression, 
such as back pain, leg weakness, urinary retention, or 
incontinence. In patients with suspected meningitis who 
require neuroimaging prior to diagnostic LP, administra- 
tion of antibiotics, preferably following blood culture, 
should precede the neuroimaging study. 

Patients receiving therapeutic anticoagulation or 
those with coagulation defects including thrombocy- 
topenia are at increased risk of post-LP spinal subdural 
or epidural hematomas, either of which can produce 



permanent nerve injury and/or paralysis. If a bleeding 
disorder is suspected, the platelet count, international 
normalized ratio (INR), and partial thromboplastin time 
should be checked prior to lumbar puncture. There are 
no data available to assess the safety of LP in patients 
with low platelet counts; a count of <20,000/|J.L is con- 
sidered to be a contraindication to LP. Bleeding compli- 
cations rarely occur in patients with platelet counts 
>50,000/|jL and an INR <1.5. Patients receiving low- 
molecular-weight heparin are at increased risk of post- 
LP spinal or epidural hematoma, and doses should be 
held for 24 h before the procedure. 

LP should not be performed through infected skin as 
organisms can be introduced into the subarachnoid 
space (SAS). 

ANALGESIA 

Anxiety and pain can be minimized prior to beginning the 
procedure. Anxiety can be allayed by the use of lorazepam, 
1—2 mg given PO 30 min prior to the procedure or IV 5 
min prior to the procedure. Topical anesthesia can be 
achieved by the application of a lidocaine -based cream. 
Lidocaine 4% is effective when applied 30 min prior to the 
procedure; lidocaine/prilocaine requires 60—120 min. The 
cream should be applied in a thick layer so that it com- 
pletely covers the skin; an occlusive dressing is used to keep 
the cream in place. 



33 



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34 POSITIONING 

Proper positioning of the patient is essential. The proce- 
dure should be performed on a firm surface; if the pro- 
cedure is to be performed at the bedside, the patient 
should be positioned at the edge of the bed and not in 
the middle. The patient is asked to lie on his or her side, 
facing away from the examiner, and to "roll up into a 
ball." The neck is gently ante-flexed and the thighs 
pulled up toward the abdomen; the shoulders and pelvis 
should be vertically aligned without forward or back- 
ward tilt (Fig. 4-1). The spinal cord terminates at 
approximately the LI vertebral level in 94% of individ- 
uals. In the remaining 6%, the conus extends to the L2- 
L3 interspace. LP is therefore performed at or below 
the L3-L4 interspace. A useful anatomic guide is a line 
drawn between the posterior superior iliac crests, which 
corresponds closely to the level of the L3-L4 inter- 
space. The interspace is chosen following gentle palpa- 
tion to identify the spinous processes at each lumbar 
level. 

An alternative to the lateral recumbent position is the 
seated position. The patient sits at the side of the bed, 
with feet supported on a chair. The patient is instructed 
to curl forward, trying to touch the nose to the umbili- 
cus. It is important that the patient not simply lean for- 
ward onto a bedside table top, as this is not an optimal 
position for opening up the spinous processes. LP is 
sometimes more easily performed in obese patients if 
they are sitting. A disadvantage of the seated position is 
that measurement of opening pressure may not be accu- 
rate. In situations in which LP is difficult using palpable 
spinal landmarks, bedside ultrasound to guide needle 
placement may be employed. 



TECHNIQUE 

Once the desired target for needle insertion has been 
identified, the examiner should put on sterile gloves. 



Vertical alignment of 
shoulders and pelvis 




L3-L4 
Inner space 

FIGURE 4-1 

Proper positioning of a patient in the lateral decubitus posi- 
tion. Note that the shoulders and hips are in a vertical plane; 
the torso is perpendicular to the bed. (From Straus etal.) 



After cleansing the skin with povidone-iodine or similar 
disinfectant, the area is draped with a sterile cloth; the 
needle insertion site is blotted dry using a sterile gauze 
pad. Proper local disinfection reduces the risk of intro- 
ducing skin bacteria into the SAS or other sites. Local 
anesthetic, typically 1% lidocaine, 3-5 mL total, is 
injected into the subcutaneous tissue; in nonemergency 
situations a topical anesthetic cream can be applied (see 
above). When time permits, pain associated with the 
injection of lidocaine can be minimized by slow, serial 
injections, each one progressively deeper than the last, 
over a period of ~5 min. Approximately 0.5—1 mL of 
lidocaine is injected at a time; the needle is not usually 
withdrawn between injections. A pause of ~15 s 
between injections helps to minimize the pain of the 
subsequent injection. The goal is to inject each mini- 
bolus of anesthetic into an area of skin that has become 
numb from the preceding injection. Approximately 5—10 
mini -boluses are injected, using a total of ~5 mL of 
lidocaine. 

If possible, the LP should be delayed for 10—15 min 
following the completion of the injection of anesthetic; 
this significantly decreases and can even eliminate pain 
from the procedure. Even a delay of 5 min will help to 
reduce pain. 

The LP needle (typically 20- to 22-gauge) is inserted 
in the midline, midway between two spinous processes, 
and slowly advanced. The bevel of the needle should be 
maintained in a horizontal position, parallel to the direc- 
tion of the dural fibers and with the flat portion of the 
bevel pointed upward; this minimizes injury to the fibers 
as the dura is penetrated. When lumbar puncture is per- 
formed in patients who are sitting, the bevel should be 
maintained in the vertical position. In most adults, the 
needle is advanced 4—5 cm (1—2 in.) before the SAS is 
reached; the examiner usually recognizes entry as a sud- 
den release of resistance, a "pop." If no fluid appears 
despite apparently correct needle placement, then the 
needle may be rotated 90°— 180°. If there is still no fluid, 
the stylet is reinserted and the needle is advanced slightly. 
Some examiners halt needle advancement periodically to 
remove the stylet and check for flow of cerebrospinal 
fluid (CSF). If the needle cannot be advanced because it 
hits bone, if the patient experiences sharp radiating pain 
down one leg, or if no fluid appears ("dry tap"), the nee- 
dle is partially withdrawn and reinserted at a different 
angle. If on the second attempt the needle still hits bone 
(indicating lack of success in introducing it between the 
spinous processes), then the needle should be completely 
withdrawn and the patient should be repositioned. The 
second attempt is sometimes more successful if the 
patient straightens the spine completely prior to reposi- 
tioning. The needle can then be reinserted at the same 
level or at an adjacent one. 

Once the SAS is reached, a manometer is attached to 
the needle and the opening pressure measured. The 



examiner should look for normal oscillations in CSF 
pressure associated with pulse and respirations. The 
upper limit of normal opening pressure with the patient 
supine is 180 mm H 2 in adults but may be as high as 
200—250 mm H 2 in obese adults. 

CSF is allowed to drip into collection tubes; it should 
not be withdrawn with a syringe. Depending on the 
clinical indication, fluid is then obtained for studies 
including: (1) cell count with differential, (2) protein and 
glucose concentrations, (3) culture (bacterial, fungal, 
mycobacterial, viral), (4) smears (e.g., Gram's and acid- 
fast stained smears), (5) antigen tests (e.g., latex aggluti- 
nation) (6) polymerase chain reaction (PCR) amplification 
of DNA or BJSTA of microorganisms (e.g., herpes sim- 
plex virus, enteroviruses), (7) antibody levels against 
microorganisms, (8) Immunoelectrophoresis for deter- 
mination of y-globulin level and oligoclonal banding, 
and (9) cytology. Although 15 mL of CSF is sufficient to 
obtain all of the listed studies, the yield of fungal and 
mycobacterial cultures and cytology increases when 
larger volumes are sampled. In general 20—30 mL may 
be safely removed from adults. 

A bloody tap due to penetration of a meningeal ves- 
sel (a "traumatic tap") may result in confusion with 
subarachnoid hemorrhage (SAH). In these situations a 
specimen of CSF should be centrifuged immediately 
after it is obtained; clear supernatant following CSF 
centrifugation supports the diagnosis of a bloody tap, 
whereas xanthochromic supernatant suggests SAH. In 
general, bloody CSF due to the penetration of a 
meningeal vessel clears gradually in successive tubes, 
whereas blood due to SAH does not. In addition to 
SAH, xanthochromic CSF may also be present in 
patients with liver disease and when the CSF protein 
concentration is markedly elevated [>1.5— 2.0 g/L 
(150-200 mg/dL)]. 

Prior to removing the LP needle, the stylet is rein- 
serted to avoid the possibility of entrapment of a 
nerve root in the dura as the needle is being with- 
drawn; entrapment could result in a dural CSF leak, 
causing headache. Some practitioners question the safety 
of this maneuver, with its potential risk of causing a 
needle-stick injury to the examiner. Injury is unlikely, 
however, given the flexibility of the small-diameter 
stylet, which tends to bend, rather than penetrate, on 
contact. Following LP, the patient is customarily posi- 
tioned in a comfortable, recumbent position for 1 h 
before rising, although recent data suggest that assum- 
ing a recumbent position may be unnecessary as it 
does not appear to affect the development of headache 
(see below). 

POST-LP HEADACHE 

The principal complication of LP is headache, occurring 
in 10—30% of patients. Younger age and female gender 



are associated with an increased risk of post-LP 35 
headache. Headache usually begins within 48 h but may 
be delayed for up to 12 days. Head pain is dramatically 
positional; it begins when the patient sits or stands 
upright; there is relief upon reclining or with abdominal 
compression. The longer the patient is upright, the 
longer the latency before head pain subsides. The pain is 
usually a dull ache but may be throbbing; its location is 
occipitofrontal. Nausea and stiff neck often accompany 
headache, and occasionally, patients report blurred 
vision, photophobia, tinnitus, and vertigo. Symptoms 
usually resolve over a few days but may on occasion per- 
sist for weeks to months. 

Post-LP headache is caused by a drop in CSF pressure 
related to persistent leakage of CSF at the site where the 
needle entered the subarachnoid space. Loss of CSF vol- 
ume decreases the brain's supportive cushion, so that 
when a patient is upright there is probably dilation and 
tension placed on the brain's anchoring structures, the 
pain-sensitive dural sinuses, resulting in pain. Although 
intracranial hypotension is the usual explanation for 
severe LP headache, the syndrome can occur in patients 
with normal CSF pressure. 

Post-LP headache usually resolves without specific 
treatment, and care is largely supportive with oral anal- 
gesics [acetaminophen, nonsteroidal anti-inflammatory 
drugs, opioids (Chap. 5)] and antiemetics. Patients may 
obtain relief by lying in a comfortable position. For 
some patients beverages with caffeine can provide tem- 
porary pain relief. 

For patients with persistent pain, treatment with IV 
caffeine (500 mg in 500 mL saline administered over 2 h) 
may be effective; atrial fibrillation is an uncommon side 
effect. For patients who do not respond to caffeine, an 
epidural blood patch accomplished by injection of 
15 mL of autologous whole blood is usually effective. 
This procedure is usually performed by a pain specialist 
or anesthesiologist. The mechanism for these treatment 
effects is not straightforward. The blood patch has an 
immediate effect, making it unlikely that sealing off a 
dural hole with blood clot is its sole mechanism of 
action. 

Strategies to decrease the incidence of post-LP 
headache are listed in Table 4-1. Use of a smaller cal- 
iber needle is associated with a lower risk: in one study, 
the risk of headache following use of a 20- or 22-gauge 
standard (Quinke) needle was 20-40%, compared to 5-12% 
when a 24- to 27-gauge needle was used. The smallest 
gauge needles usually require the use of an introducer 
needle and are associated with a slower CSF flow rate. 
Use of an "atraumatic" (Sprotte, "pencil point," or "non- 
cutting") needle also reduces the incidence of moderate 
to severe headache compared with standard LP (Quinke, 
or "traumatic") needles (Fig. 4-2). However, because 
atraumatic needles are more difficult to use, more 
attempts may be required to perform the LP, particularly 



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36 TABLE 4-1 



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REDUCING THE INCIDENCE OF POST-LP HEADACHE 



Effective Strategies 

Use of small-diameter needle (22-gauge or smaller) 
Use of atraumatic needle (Sprotte and others) 
Replacement of stylet prior to removal of needle 
Insertion of needle with bevel oriented in a cephalad to 
caudad direction (when using standard needle) 
Ineffective Strategies 

Bed rest (up to 4 h) following LP 
Supplemental fluids 

Minimizing the volume of spinal fluid removed 
Immediate mobilization following LP 



in overweight patients. It may also be necessary to use 
an introducer with the atraumatic needle, which does 
not have the customary cutting, beveled tip. There is a 
low risk of needle damage, e.g., breakage, with the Sprotte 
atraumatic needle. 

Another strategy to decrease the incidence of headache 
is to replace the stylet before removing the LP needle. 
Studies comparing mobilization immediately following 
LP with bed rest for up to 4 h show no significant dif- 
ferences in the incidence of headache, suggesting that 
the customary practice of remaining in a recumbent posi- 
tion post-LP may be unnecessary. 



NORMAL VALUES 

(See Table 4-2) In uninfected CSF, the normal -white 
blood cell count is fewer than five mononuclear cells 
(lymphocytes and monocytes) per |TL. Polymor- 
phonuclear leukocytes (PMNs) are not found in nor- 
mal unconcentrated CSF; however, rare PMNs can be 
found in centrifuged or concentrated CSF specimens 



TABLE 4-2 



CEREBROSPINAL FLUID 3 



CONVENTIONAL 



CONSTITUENT 


SI UNITS 


UNITS 


Glucose 


2.22-3.89 mmol/L 


40-70 mg/dL 


Lactate 


1-2 mmol/L 


10-20 mg/dL 


Total protein 






Lumbar 


0.15-0.5 g/L 


15-50 mg/dL 


Cisternal 


0.15-0.25 g/L 


15-25 mg/dL 


Ventricular 


0.06-0.15 g/L 


6-15 mg/dL 


Albumin 


0.066-0.442 g/L 


6.6-44.2 mg/dL 


IgG 


0.009-0.057 g/L 


0.9-5.7 mg/dL 


IgG index" 


0.29-0.59 




Oligoclonal 


<2 bands not 




bands (OGB) 


present in 
matched serum 
sample 




Ammonia 


15-47 u.mol/L 


25-80 u.g/dL 


CSF pressure 




50-1 80 mm H 2 


CSF volume 


-150 mL 




(adult) 






Red blood cells 








Leukocytes 






Total 


0-5 mononuclear 
cells per mm 3 




Differential 






Lymphocytes 


60-70% 




Monocytes 


30-50% 




Neutrophils 


None 





a Since cerebrospinal fluid concentrations are equilibrium values, 
measurements of the same parameters in blood plasma obtained at 
the same time are recommended. However, there is a time lag in 
attainment of equilibrium, and cerebrospinal levels of plasma con- 
stituents that can fluctuate rapidly (such as plasma glucose) may not 
achieve stable values until after a significant lag phase. 
b lgG index = CSF lgG(mg/dL) x serum albumin(g/dL)/Serum lgG(g/dL) 
x CSF albumin(mg/dL). 



such as those utilized for cytologic examination. Red 
blood cells (RBCs) are not normally present in CSF; 
if RBCs are present from a traumatic tap, their num- 
ber decreases as additional CSF is collected. CSF 
glucose concentrations <2.2 mmol/L (<40 mg/dL) 
are abnormal. 






FIGURE 4-2 

Comparison of the standard ("traumatic" or Quinke) LP 
needle with the "atraumatic" (Sprotte). The atraumatic 
needle has its opening on the top surface of the needle, a 
design intended to reduce the chance of cutting dural fibers 
that, by protruding through the dura, could be responsible 
for subsequent CSF fluid leak and post-LP headache. (From 
Thomas et al.) 



FURTHER READINGS 

ARMON C, EVANS RW: Addendum to assessment: Prevention of 
post-lumbar puncture headaches: Report of the Therapeutics 
and Technology Assessment Subcommittee of the American 
Academy of Neurology. Neurology 65:510, 2005 

ELLENBY MS et al: Lumbar puncture (video). N Engl J Med 
355:el2,2006 

EVANS RW et al: Assessment: Prevention of post-lumbar puncture 
headaches: Report of the Therapeutics and Technology Assess- 
ment Subcommittee of the American Academy of Neurology. 
Neurology 55:909, 2000 



FERRE RM, SWEENEY TW: Emergency physicians can easily obtain 

ultrasound images of anatomical landmarks relevant to lumbar 

puncture. Am J Emerg Med 25: 291, 2007 
LAVI R et al: Standard vs atraumatic Whitacre needle for diagnostic 

lumbar puncture: A randomized trial. Neurology 67:1492, 2006 
RlCHMAN JM et al: Bevel direction and postdural puncture 

headache: A meta-analysis. Neurologist 12:224, 2006 
STRAUS SE et al: How do I perform a lumbar puncture and analyze 

the results to diagnose bacterial meningitis? JAMA 296:2012, 2006 



STRUPP M et al: Incidence of post-lumbar puncture syndrome "ll 

reduced by reinserting the stylet: A randomized prospective study 

of 600 patients.J Neurol 245:589, 1998 
THOMAS SF et al: Randomised controlled trial of atraumatic versus 

standard needles for diagnostic lumbar puncture. BMJ 321:986, 

2000 
Turnbull DK, Shepherd DB: Post-dural puncture headache: 

Pathogenesis, prevention and treatment. Br J Anaesth 91:718, 

2003 



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Howard L Fields ■ Joseph B. Martin 



The Pain Sensory System 40 

Peripheral Mechanisms 40 

Central Mechanisms 41 

Pain Modulation 43 

Neuropathic Pain 44 

Chronic Pain 47 

Further Readings 49 



The task of medicine is to preserve and restore health 
and to relieve suffering. Understanding pain is essential 
to both these goals. Because pain is universally under- 
stood as a signal of disease, it is the most common symp- 
tom that brings a patient to a physician's attention. The 
function of the pain sensory system is to protect the 
body and maintain homeostasis. It does this by detecting, 
localizing, and identifying tissue -damaging processes. Since 
different diseases produce characteristic patterns of tissue 
damage, the quality, time course, and location of a patient's 
pain complaint and the location of tenderness provide 
important diagnostic clues and are used to evaluate the 
response to treatment. Once this information is obtained, 
it is the obligation of the physician to provide rapid and 
effective pain relief. 



THE PAIN SENSORY SYSTEM 

Pain is an unpleasant sensation localized to a part of the 
body. It is often described in terms of a penetrating or 
tissue-destructive process (e.g., stabbing, burning, twist- 
ing, tearing, squeezing) and/or of a bodily or emotional 
reaction (e.g., terrifying, nauseating, sickening). Further- 
more, any pain of moderate or higher intensity is accom- 
panied by anxiety and the urge to escape or terminate 
the feeling. These properties illustrate the duality of pain: 
it is both sensation and emotion. When acute, pain is 
characteristically associated with behavioral arousal and a 



40 



stress response consisting of increased blood pressure, 
heart rate, pupil diameter, and plasma Cortisol levels. In 
addition, local muscle contraction (e.g., limb flexion, 
abdominal wall rigidity) is often present. 



PERIPHERAL MECHANISMS 
The Primary Afferent Nociceptor 

A peripheral nerve consists of the axons of three different 
types of neurons: primary sensory afferents, motor neu- 
rons, and sympathetic postganglionic neurons (Fig. 5-1). 
The cell bodies of primary sensory afferents are located in 
the dorsal root ganglia in the vertebral foramina. The pri- 
mary afferent axon bifurcates to send one process into the 
spinal cord and the other to innervate tissues. Primary affer- 
ents are classified by their diameter, degree of myelination, 
and conduction velocity. The largest-diameter fibers, 
A-beta (A(3), respond maximally to light touch and/or 
moving stimuli; they are present primarily in nerves that 
innervate the skin. In normal individuals, the activity of 
these fibers does not produce pain. There are two other 
classes of primary afferents: the small-diameter myelinated 
A-delta (A8) and the unmyelinated (C fiber) axons 
(Fig. 5-1). These fibers are present in nerves to the skin 
and to deep somatic and visceral structures. Some tissues, 
such as the cornea, are innervated only by A8 and C 
afferents. Most A8 and C afferents respond maximally only 
to intense (painful) stimuli and produce the subjective 



Dorsal root 
ganglion 



41 



Peripheral nerve 




Spinal 
cord 



Sympathetic 
postganglionic 

FIGURE 5-1 

Components of a typical cutaneous nerve. There are two 
distinct functional categories of axons: primary afferents 
with cell bodies in the dorsal root ganglion, and sympa- 
thetic postganglionic fibers with cell bodies in the sympathetic 



Sympathetic 
preganglionic 



ganglion. Primary afferents include those with large- 
diameter myelinated (Ap), small-diameter myelinated (A8), 
and unmyelinated (C) axons. All sympathetic postganglionic 
fibers are unmyelinated. 



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experience of pain when they are electrically stimulated; 
this defines them as primary afferent nociceptors (pain 
receptors). The ability to detect painful stimuli is com- 
pletely abolished when A8 and C axons are blocked. 

Individual primary afferent nociceptors can respond 
to several different types of noxious stimuli. For exam- 
ple, most nociceptors respond to heating, intense cold, 
intense mechanical stimuli such as a pinch, and applica- 
tion of irritating chemicals including ATP, serotonin, 
bradykinin and histamine. 

Sensitization 

When intense, repeated, or prolonged stimuli are applied 
to damaged or inflamed tissues, the threshold for activat- 
ing primary afferent nociceptors is lowered and the fre- 
quency of firing is higher for all stimulus intensities. 
Inflammatory mediators such as bradykinin, nerve growth 
factor, some prostaglandins, and leukotrienes contribute 
to this process, which is called sensitization. In sensitized 
tissues, normally innocuous stimuli can produce pain. 
Sensitization is a clinically important process that con- 
tributes to tenderness, soreness, and hyperalgesia. A strik- 
ing example of sensitization is sunburned skin, in which 
severe pain can be produced by a gentle slap on the 
back or a warm shower. 

Sensitization is of particular importance for pain and 
tenderness in deep tissues. Viscera are normally relatively 
insensitive to noxious mechanical and thermal stimuli, 
although hollow viscera do generate significant discomfort 
when distended. In contrast, when affected by a disease 
process with an inflammatory component, deep structures 
such as joints or hollow viscera characteristically become 
exquisitely sensitive to mechanical stimulation. 

A large proportion of A8 and C afferents innervating 
viscera are completely insensitive in normal noninjured, 



noninflamed tissue. That is, they cannot be activated by 
known mechanical or thermal stimuli and are not sponta- 
neously active. However, in the presence of inflammatory 
mediators, these afferents become sensitive to mechanical 
stimuli. Such afferents have been termed silent nociceptors, 
and their characteristic properties may explain how under 
pathologic conditions the relatively insensitive deep struc- 
tures can become the source of severe and debilitating pain 
and tenderness. Low pH, prostaglandins, leukotrienes, and 
other inflammatory mediators such as bradykinin play a 
significant role in sensitization. 

Nociceptor-lnduced Inflammation 

Primary afferent nociceptors also have a neuroeffector func- 
tion. Most nociceptors contain polypeptide mediators 
that are released from their peripheral terminals when 
they are activated (Fig. 5-2). An example is substance P, an 
11-amino-acid peptide. Substance P is released from pri- 
mary afferent nociceptors and has multiple biologic activi- 
ties. It is a potent vasodilator, degranulates mast cells, is a 
chemoattractant for leukocytes, and increases the produc- 
tion and release of inflammatory mediators. Interestingly, 
depletion of substance P from joints reduces the severity 
of experimental arthritis. Primary afferent nociceptors are 
not simply passive messengers of threats to tissue injury 
but also play an active role in tissue protection through these 
neuroeffector functions. 

CENTRAL MECHANISMS 

The Spinal Cord and Referred Pain 

The axons of primary afferent nociceptors enter the spinal 
cord via the dorsal root. They terminate in the dorsal 
horn of the spinal gray matter (Fig. 5-3). The terminals 
of primary afferent axons contact spinal neurons that 



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42 



Primary activation 



Skin 



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/ 5HT i-Jj^ 

Platelet 



FIGURE 5-2 

Events leading to activation, sensitization, and spread of 
sensitization of primary afferent nociceptor terminals. 

A. Primary activation by intense pressure and consequent cell 
damage. Cell damage induces lower pH (H + ) and leads to 
release of potassium (K + ) and to synthesis of prostaglandins 
(PG) and bradykinin (BK). Prostaglandins increase the sensitiv- 
ity of the terminal to bradykinin and other pain-producing sub- 
stances. B. Secondary activation. Impulses generated in the 
stimulated terminal propagate not only to the spinal cord but 
also into other terminal branches where they induce the release 
of peptides, including substance P (SP). Substance P causes 
vasodilation and neurogenic edema with further accumulation 
of bradykinin. Substance P also causes the release of hista- 
mine (H) from mast cells and serotonin (5HT) from platelets. 



transmit the pain signal to brain sites involved in pain 
perception. When primary afferents are activated by nox- 
ious stimuli, they release neurotransmitters from their 
terminals that excite the spinal cord neurons. The major 
neurotransmitter they release is glutamate, which rapidly 
excites dorsal horn neurons. Primary afferent nociceptor 
terminals also release peptides, including substance P and 




Viscus Anterolateral 

tract axon 
FIGURE 5-3 

The convergence-projection hypothesis of referred pain. 

According to this hypothesis, visceral afferent nociceptors con- 
verge on the same pain-projection neurons as the afferents 
from the somatic structures in which the pain is perceived. The 
brain has no way of knowing the actual source of input and 
mistakenly "projects" the sensation to the somatic structure. 



calcitonin gene-related peptide, which produce a slower 
and longer-lasting excitation of the dorsal horn neurons. 
The axon of each primary afferent contacts many spinal 
neurons, and each spinal neuron receives convergent 
inputs from many primary afferents. 

The convergence of sensory inputs to a single spinal 
pain-transmission neuron is of great importance because 
it underlies the phenomenon of referred pain. All spinal 
neurons that receive input from the viscera and deep 
musculoskeletal structures also receive input from the 
skin. The convergence patterns are determined by the 
spinal segment of the dorsal root ganglion that supplies 
the afferent innervation of a structure. For example, the 
afferents that supply the central diaphragm are derived 
from the third and fourth cervical dorsal root ganglia. 
Primary afferents with cell bodies in these same ganglia 
supply the skin of the shoulder and lower neck. Thus, 
sensory inputs from both the shoulder skin and the cen- 
tral diaphragm converge on pain-transmission neurons in 
the third and fourth cervical spinal segments. Because of 
this convergence and the fact that the spinal neurons are most 
often activated by inputs from the skin, activity evoked in spinal 
neurons by input from deep structures is mislocalized by the 
patient to a place that is roughly coextensive with the region of 
skin innervated by the same spinal segment. Thus, inflamma- 
tion near the central diaphragm is usually reported as dis- 
comfort near the shoulder. This spatial displacement of 
pain sensation from the site of the injury that produces it 
is known as referred pain. 

Ascending Pathways for Pain 

A majority of spinal neurons contacted by primary 
afferent nociceptors send their axons to the contralateral 



Thalamus 




Midbrain 



Medulla 




Spinal 

cord \ J 

A B ^— -' 

FIGURE 5-4 

Pain transmission and modulatory pathways. A. Transmis- 
sion system for nociceptive messages. Noxious stimuli acti- 
vate the sensitive peripheral ending of the primary afferent 
nociceptor by the process of transduction. The message is 
then transmitted over the peripheral nerve to the spinal cord, 
where it synapses with cells of origin of the major ascending 
pain pathway, the spinothalamic tract. The message is relayed 
in the thalamus to the anterior cingulate (C), frontal insular (F), 
and somatosensory cortex (SS). B. Pain-modulation network. 
Inputs from frontal cortex and hypothalamus activate cells in 
the midbrain that control spinal pain-transmission cells via 
cells in the medulla. 



thalamus. These axons form the contralateral spinothala- 
mic tract, which lies in the anterolateral white matter of 
the spinal cord, the lateral edge of the medulla, and the 
lateral pons and midbrain. The spinothalamic pathway is 
crucial for pain sensation in humans. Interruption of this 
pathway produces permanent deficits in pain and tem- 
perature discrimination. 

Spinothalamic tract axons ascend to several regions of 
the thalamus. There is tremendous divergence of the pain 
signal from these thalamic sites to broad areas of the 
cerebral cortex that subserve different aspects of the pain 
experience (Fig. 5-4). One of the thalamic projections is 
to the somatosensory cortex. This projection mediates 
the purely sensory aspects of pain, i.e., its location, inten- 
sity, and quality. Other thalamic neurons project to corti- 
cal regions that are linked to emotional responses, such as 
the cingulate gyrus and other areas of the frontal lobes, 
including the insular cortex. These pathways to the frontal 
cortex subserve the affective or unpleasant emotional 



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dimension of pain. This affective dimension of pain pro- 43 
duces suffering and exerts potent control of behavior. 
Because of this dimension, fear is a constant companion 
of pain. 

PAIN MODULATION 

The pain produced by injuries of similar magnitude is 
remarkably variable in different situations and in differ- 
ent individuals. For example, athletes have been known 
to sustain serious fractures with only minor pain, and 
Beecher's classic World War II survey revealed that many 
soldiers in battle were unbothered by injuries that would 
have produced agonizing pain in civilian patients. Fur- 
thermore, even the suggestion of relief can have a signifi- 
cant analgesic effect (placebo) . On the other hand, many 
patients find even minor injuries (such as venipuncture) 
frightening and unbearable, and the expectation of pain 
has been demonstrated to induce pain without a noxious 
stimulus. 

The powerful effect of expectation and other psycho- 
logical variables on the perceived intensity of pain implies 
the existence of brain circuits that can modulate the 
activity of the pain-transmission pathways. One of these 
circuits has links in the hypothalamus, midbrain, and 
medulla, and it selectively controls spinal pain-transmis- 
sion neurons through a descending pathway (Fig. 5-4). 

Human brain imaging studies have implicated this 
pain-modulating circuit in the pain-relieving effect of 
attention, suggestion, and opioid analgesic medications. 
Furthermore, each of the component structures of the 
pathway contains opioid receptors and is sensitive to 
the direct application of opioid drugs. In animals, 
lesions of the system reduce the analgesic effect of sys- 
temically administered opioids such as morphine. Along 
with the opioid receptor, the component nuclei of this 
pain-modulating circuit contain endogenous opioid 
peptides such as the enkephalins and (3-endorphin. 

The most reliable way to activate this endogenous 
opioid-mediated modulating system is by prolonged pain 
and/or fear. There is evidence that pain-relieving endoge- 
nous opioids are released following surgical procedures 
and in patients given a placebo for pain relief. 

Pain-modulating circuits can enhance as well as suppress 
pain. Both pain-inhibiting and pain-facilitating neurons in 
the medulla project to and control spinal pain-transmission 
neurons. Since pain-transmission neurons can be activated 
by modulatory neurons, it is theoretically possible to gener- 
ate a pain signal with no peripheral noxious stimulus. In 
fact, human functional imaging studies have demonstrated 
increased activity in this circuit during migraine headache. 
A central circuit that facilitates pain could account for the 
finding that pain can be induced by suggestion or 
enhanced by expectation, and it could provide a framework 
for understanding how psychological factors can contribute 
to chronic pain. 



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44 NEUROPATHIC PAIN 

Lesions of the peripheral or central nervous pathways for 
pain typically result in a loss or impairment of pain sen- 
sation. Paradoxically damage to or dysfunction of these 
pathways can produce pain. For example, damage to 
peripheral nerves, as occurs in diabetic neuropathy, or to 
primary afferents, as in herpes zoster, can result in pain 
that is referred to the body region innervated by the 
damaged nerves. Though rare, pain may also be produced 
by damage to the central nervous system, particularly the 
spinothalamic pathway or thalamus. Such neuropathic 
pains are often severe and are notoriously intractable to 
standard treatments for pain. 

Neuropathic pains typically have an unusual burning, 
tingling, or electric shock— like quality and may be trig- 
gered by very light touch. These features are rare in other 
types of pain. On examination, a sensory deficit is char- 
acteristically present in the area of the patient's pain. 
Hyperpathia is also characteristic of neuropathic pain; 
patients often complain that the very lightest moving 
stimuli evoke exquisite pain (allodynia). In this regard it 
is of clinical interest that a topical preparation of 5% 
lidocaine in patch form is effective for patients with pos- 
therpetic neuralgia who have prominent allodynia. 

A variety of mechanisms contribute to neuropathic pain. 
As with sensitized primary afferent nociceptors, damaged 
primary afferents, including nociceptors, become highly 
sensitive to mechanical stimulation and begin to generate 
impulses in the absence of stimulation. There is evidence 
that this increased sensitivity and spontaneous activity is 
due to an increased concentration of sodium channels. 
Damaged primary afferents may also develop sensitivity to 
norepinephrine. Interestingly, spinal cord pain-transmission 
neurons cut off from their normal input may also become 
spontaneously active. Thus, both central and peripheral ner- 
vous system hyperactivity contribute to neuropathic pain. 



Sympathetically Maintained Pain 

Patients with peripheral nerve injury can develop a 
severe burning pain (causalgia) in the region innervated 
by the nerve. The pain typically begins after a delay of 
hours to days or even weeks. The pain is accompanied by 
swelling of the extremity, periarticular osteoporosis, and 
arthritic changes in the distal joints. The pain is dramati- 
cally and immediately relieved by blocking the sympa- 
thetic innervation of the affected extremity. Damaged 
primary afferent nociceptors acquire adrenergic sensitiv- 
ity and can be activated by stimulation of the sympa- 
thetic outflow. A similar syndrome called reflex sympathetic 
dystrophy can be produced -without obvious nerve dam- 
age by a variety of injuries, including fractures of bone, 
soft tissue trauma, myocardial infarction, and stroke. 
Although the pathophysiology of this condition is poorly 
understood, the pain and the signs of inflammation are 



rapidly relieved by blocking the sympathetic nervous sys- 
tem. This implies that sympathetic activity can activate 
undamaged nociceptors when inflammation is present. 
Signs of sympathetic hyperactivity should be sought in 
patients with posttraumatic pain and inflammation and 
no other obvious explanation. 



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Treatment : 
ACUTE PAIN 



The ideal treatment for any pain is to remove the cause; 
thus, diagnosis should always precede treatment plan- 
ning. Sometimes treating the underlying condition does 
not immediately relieve pain. Furthermore, some condi- 
tions are so painful that rapid and effective analgesia is 
essential (e.g., the postoperative state, burns, trauma, 
cancer, sickle cell crisis). Analgesic medications are a first 
line of treatment in these cases, and all practitioners 
should be familiar with their use. 

ASPIRIN, ACETAMINOPHEN, AND NONS- 
TEROIDAL ANTI-INFLAMMATORY AGENTS 
(NSAIDS) These drugs are considered together 
because they are used for similar problems and may have 
a similar mechanism of action (Table 5-1). All these com- 
pounds inhibit cyclooxygenase (COX), and, except for 
acetaminophen, all have anti-inflammatory actions, espe- 
cially at higher dosages. They are particularly effective for 
mild to moderate headache and for pain of muscu- 
loskeletal origin. 

Since they are effective for these common types of 
pain and are available without prescription, COX 
inhibitors are by far the most commonly used analgesics. 
They are absorbed well from the gastrointestinal tract 
and, with occasional use, have only minimal side effects. 
With chronic use, gastric irritation is a common side 
effect of aspirin and NSAIDs and is the problem that 
most frequently limits the dose that can be given. Gastric 
irritation is most severe with aspirin, which may cause 
erosion and ulceration of the gastric mucosa leading to 
bleeding or perforation. Because aspirin irreversibly 
acetylates platelets and thereby interferes with coagula- 
tion of the blood, gastrointestinal bleeding is a particular 
risk. Increased age and history of gastrointestinal disease 
increase the risks of aspirin and NSAIDs. In addition to 
NSAIDs' well-known gastrointestinal toxicity, nephrotoxi- 
city is a significant problem for patients using them on a 
chronic basis, and patients at risk for renal insufficiency 
should be monitored closely. NSAIDs also cause an 
increase in blood pressure in a significant number of 
individuals. Long-term treatment with NSAIDs requires 
regular blood pressure monitoring and treatment if nec- 
essary. Although toxic to the liver when taken in a high 
dose, acetaminophen rarely produces gastric irritation 
and does not interfere with platelet function. 



TABLE 5-1 



DRUGS FOR RELIEF OF PAIN 



45 



GENERIC NAME 


DOSE, mg 


INTERVAL 


COMMENTS 


Nonnarcotic Analgesics: Usual Doses and Intervals 




Acetylsalicylic acid 


650 PO 


q4h 


Enteric-coated preparations available 


Acetaminophen 


650 PO 


q4h 


Side effects uncommon 


Ibuprofen 


400 PO 


q4-6h 


Available without prescription 


Naproxen 


250-500 PO 


q 12 h 


Delayed effects may be due to long half-life 


Fenoprofen 


200 PO 


q4-6h 


Contraindicated in renal disease 


Indomethacin 


25-50 PO 


q8h 


Gastrointestinal side effects common 


Ketorolac 


15-60 I M/IV 


q4-6h 


Available for parenteral use 


Celecoxib 


100-200 PO 


q 12-24 h 


Useful for arthritis 


Valdecoxib 


10-20 PO 


q 12-24 h 


Removed from U.S. market in 2005 



GENERIC NAME 


PARENTERAL DOSE, 


mg 


PO DOSE, mg 


COMMENTS 


Narcotic Analgesics: 


Usual Doses and Intervals 






Codeine 


30-60 q 4 h 




30-60 q 4 h 


Nausea common 


Oxycodone 


— 




5-10q4-6h 


Usually available with acetaminophen or aspirin 


Morphine 


10q4h 




60q4h 




Morphine sustained 


— 




30-200 bid 


Oral slow-release preparation 


release 






totid 




Hydromorphone 


1-2 q 4 h 




2-4 q 4 h 


Shorter acting than morphine sulfate 


Levorphanol 


2 q 6-8 h 




4 q 6-8 h 


Longer acting than morphine sulfate; absorbed well PO 


Methadone 


10q6-8h 




20 q 6-8 h 


Delayed sedation due to long half-life 


Meperidine 


75-1 00 q 3-4 h 




300 q 4 h 


Poorly absorbed PO; normeperidine a toxic metabolite 


Butorphanol 


— 




1-2 q4h 


Intranasal spray 


Fentanyl 


25-100 u.g/h 




— 


72-h Transdermal patch 


Tramadol 


— 




50-100 q 4-6 h 


Mixed opioid/adrenergic action 



UPTAKE BLOCKADE 



GENERIC NAME 5-HT 



NE 



SEDATIVE 
POTENCY 



ANTICHOLINERGIC 
POTENCY 



ORTHOSTATIC 
HYPOTENSION 



CARDIAC 
ARRHYTHMIA 



AVE. DOSE, 
mg/d 



RANGE, 
mg/d 



Antidepressants 3 
















Doxepin 


++ 


+ 


High 


Moderate 


Moderate 


Less 


200 


75-400 


Amitriptyline 


++++ 


++ 


High 


Highest 


Moderate 


Yes 


150 


25-300 


Imipramine 


++++ 


++ 


Moderate 


Moderate 


High 


Yes 


200 


75-400 


Nortriptyline 


+++ 


++ 


Moderate 


Moderate 


Low 


Yes 


100 


40-150 


Desipramine 


+++ 


++++ 


Low 


Low 


Low 


Yes 


150 


50-300 


Venlafaxine 


+++ 


++ 


Low 


None 


None 


No 


150 


75-400 


Duloxetine 


+++ 


+++ 


Low 


None 


None 


No 


40 


30-60 



GENERIC NAME 



PO DOSE, mg 



INTERVAL 



GENERIC NAME 



PO DOSE, mg 



INTERVAL 



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O 



O 



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Anticonvulsants and Antiarrhythmics 3 

Phenytoin 300 daily/qhs 

Carbamazepine 200-300 q 6 h 

Oxcarbazepine 300 bid 



Clonazepam 
Gabapentin" 
Pregabalin 



600-1200 
150-600 



q6h 
q8h 
bid 



Antidepressants, anticonvulsants, and antiarrhythmics have not been approved by the U.S. Food and Drug Administration (FDA) for the treat- 
ment of pain. 

b Gabapentin in doses up to 1800 mg/d is FDA approved for postherpetic neuralgia. 
Note: 5-HT, serotonin; NE, norepinephrine. 



The introduction of a parenteral form of NSAID, 
ketorolac, extends the usefulness of this class of com- 
pounds in the management of acute severe pain. 
Ketorolac is sufficiently potent and rapid in onset to 
supplant opioids for many patients with acute severe 
headache and musculoskeletal pain. 



There are two major classes of COX: COX-1 is constitu- 
tively expressed, and COX-2 is induced in the inflamma- 
tory state. COX-2-selective drugs have moderate anal- 
gesic potency and produce less gastric irritation than 
the nonselective COX inhibitors. It is not yet clear 
whether the use of COX-2-selective drugs is associated 



46 



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with a lower risk of nephrotoxicity compared to nonse- 
lective NSAIDs. On the other hand, COX-2-selective 
drugs offer a significant benefit in the management of 
acute postoperative pain because they do not affect 
blood coagulation. This is a situation in which the nonse- 
lective COX inhibitors would be contraindicated because 
they impair platelet-mediated blood clotting and are 
thus associated with increased bleeding at the operative 
site. COX-2 inhibitors, including celecoxib (Celebrex), and 
valdecoxib (Bextra),are associated with increased cardio- 
vascular risk. It is possible that this is a class effect of 
NSAIDs, excluding aspirin. These drugs are contraindi- 
cated in patients in the immediate period after coronary 
artery bypass surgery and should be used with caution 
in patients having a history of or significant risk factors 
for cardiovascular disease. 

OPIOID ANALGESICS Opioids are the most 
potent pain-relieving drugs currently available. Further- 
more, of all analgesics, they have the broadest range of 
efficacy, providing the most reliable and effective 
method for rapid pain relief. Although side effects are 
common, they are usually not serious except for respi- 
ratory depression and can be reversed rapidly with the 
narcotic antagonist naloxone. The physician should not 
hesitate to use opioid analgesics in patients with acute 
severe pain. Table 5-1 lists the most commonly used 
opioid analgesics. 

Opioids produce analgesia by actions in the central 
nervous system. They activate pain-inhibitory neurons 
and directly inhibit pain-transmission neurons. Most of 
the commercially available opioid analgesics act at the 
same opioid receptor (u-receptor), differing mainly in 
potency, speed of onset, duration of action, and optimal 
route of administration. Although the dose-related side 
effects (sedation, respiratory depression, pruritus, con- 
stipation) are similar among the different opioids, some 
side effects are due to accumulation of nonopioid 
metabolites that are unique to individual drugs. One 
striking example of this is normeperidine, a metabolite 
of meperidine. Normeperidine produces hyperexcitabil- 
ity and seizures that are not reversible with naloxone. 
Normeperidine accumulation is increased in patients 
with renal failure. 

The most rapid relief with opioids is obtained by 
intravenous administration; relief with oral administra- 
tion is significantly slower. Common side effects include 
nausea, vomiting, constipation, and sedation. The most 
serious side effect is respiratory depression. Patients with 
any form of respiratory compromise must be kept under 
close observation following opioid administration; an 
oxygen saturation monitor may be useful. The opioid 
antagonist naloxone should be readily available. Opioid 
effects are dose-related, and there is great variability 
among patients in the doses that relieve pain and produce 



side effects. Because of this, initiation of therapy requires 
titration to optimal dose and interval. The most impor- 
tant principle is to provide adequate pain relief. This 
requires determining whether the drug has adequately 
relieved the pain and the duration of the relief. The 
most common error made by physicians in manag- 
ing severe pain with opioids is to prescribe an inade- 
quate dose. Since many patients are reluctant to 
complain, this practice leads to needless suffering. In 
the absence of sedation at the expected time of peak 
effect, a physician should not hesitate to repeat the ini- 
tial dose to achieve satisfactory pain relief. 

An innovative approach to the problem of achieving 
adequate pain relief is the use of patient-controlled anal- 
gesia (PCA). PCA requires a device that can deliver a base- 
line continuous dose of an opioid drug, as well as prepro- 
grammed additional doses whenever the patient pushes 
a button. The patient can then titrate the dose to the 
optimal level. This approach is used most extensively for 
the management of postoperative pain, but there is no 
reason why it should not be used for any hospitalized 
patient with persistent severe pain. PCA is also used for 
short-term home care of patients with intractable pain, 
such as that caused by metastatic cancer. 

Because of patient variability in analgesia requirement, 
intravenous PCA is generally begun after the patient's 
pain has been controlled. The bolus dose of the drug 
(typically 1 mg morphine or 40 jag fentanyl) can then be 
delivered repeatedly as needed. To prevent overdosing, 
PCA devices are programmed with a lockout period after 
each demand dose is delivered (5-1 min) and a limit on 
the total dose delivered per hour. While some have advo- 
cated the use of a simultaneous background infusion of 
the PCA drug, this increases the risk of respiratory 
depression and has not been shown to increase the 
overall efficacy of the technique. 

Many physicians, nurses, and patients have a certain 
trepidation about using opioids that is based on an 
exaggerated fear of addiction. In fact, there is a vanish- 
ingly small chance of patients becoming addicted to 
narcotics as a result of their appropriate medical use. 

The availability of new routes of administration has 
extended the usefulness of opioid analgesics. Most 
important is the availability of spinal administration. 
Opioids can be infused through a spinal catheter placed 
either intrathecally or epidurally. By applying opioids 
directly to the spinal cord, regional analgesia can be 
obtained using a relatively low total dose. In this way, 
such side effects as sedation, nausea, and respiratory 
depression can be minimized. This approach has been 
used extensively in obstetric procedures and for lower- 
body postoperative pain. Opioids can also be given 
intranasally (butorphanol), rectally, and transdermal^ 
(fentanyl), thus avoiding the discomfort of frequent 
injections in patients who cannot be given oral medication. 



The fentanyl transdermal patch has the advantage of 
providing fairly steady plasma levels, which maximizes 
patient comfort. 

OPIOID AND COX INHIBITOR COMBINA- 
TIONS When used in combination, opioids and COX 
inhibitors have additive effects. Because a lower dose of 
each can be used to achieve the same degree of pain 
relief, and their side effects are nonadditive, such combi- 
nations can be used to lower the severity of dose- 
related side effects. Fixed-ratio combinations of an opi- 
oid with acetaminophen carry a special risk. Dose 
escalation as a result of increased severity of pain or 
decreased opioid effect as a result of tolerance may lead 
to levels of acetaminophen that are toxic to the liver. 



CHRONIC PAIN 

Managing patients with chronic pain is intellectually and 
emotionally challenging. The patient's problem is often 
difficult to diagnose; such patients are demanding of the 
physician's time and often appear emotionally distraught. 
The traditional medical approach of seeking an obscure 
organic pathology is usually unhelpful. On the other hand, 
psychological evaluation and behaviorally based treatment 
paradigms are frequently helpful, particularly in the setting 
of a multidisciplinary pain-management center. 

There are several factors that can cause, perpetuate, or 
exacerbate chronic pain. First, of course, the patient may 
simply have a disease that is characteristically painful for 
which there is presently no cure. Arthritis, cancer, migraine 
headaches, fibromyalgia, and diabetic neuropathy are exam- 
ples of this. Second, there may be secondary perpetuating 
factors that are initiated by disease and persist after that 
disease has resolved. Examples include damaged sensory 
nerves, sympathetic efferent activity, and painful reflex mus- 
cle contraction. Finally, a variety of psychological condi- 
tions can exacerbate or even cause pain. 

There are certain areas to which special attention should 
be paid in the medical history. Because depression is the 
most common emotional disturbance in patients with chronic 
pain, patients should be questioned about their mood, 
appetite, sleep patterns, and daily activity. A simple standard- 
ized questionnaire, such as the Beck Depression Inventory, 
can be a useful screening device. It is important to remember 
that major depression is a common, treatable, and poten- 
tially fatal illness. 

Other clues that a significant emotional disturbance is 
contributing to a patient's chronic pain complaint include: 
pain that occurs in multiple unrelated sites; a pattern of 
recurrent, but separate, pain problems beginning in child- 
hood or adolescence; pain beginning at a time of emotional 
trauma, such as the loss of a parent or spouse; a history of 



physical or sexual abuse; and past or present substance 
abuse. 

On examination, special attention should be paid to 
whether the patient guards the painful area and whether 
certain movements or postures are avoided because of pain. 
Discovering a mechanical component to the pain can be 
useful both diagnostically and therapeutically. Painful areas 
should be examined for deep tenderness, noting whether 
this is localized to muscle, ligamentous structures, or 
joints. Chronic myofascial pain is very common, and in 
these patients deep palpation may reveal highly localized 
trigger points that are firm bands or knots in muscle. 
Relief of the pain following injection of local anesthetic 
into these trigger points supports the diagnosis. A neuro- 
pathic component to the pain is indicated by evidence of 
nerve damage, such as sensory impairment, exquisitely sen- 
sitive skin, weakness and muscle atrophy, or loss of deep 
tendon reflexes. Evidence suggesting sympathetic nervous 
system involvement includes the presence of diffuse swelling, 
changes in skin color and temperature, and hypersensitive 
skin and joint tenderness compared with the normal side. 
Relief of the pain with a sympathetic block is diagnostic. 

A guiding principle in evaluating patients with chronic 
pain is to assess both emotional and organic factors before 
initiating therapy. Addressing these issues together, rather 
than waiting to address emotional issues after organic 
causes of pain have been ruled out, improves compliance in 
part because it assures patients that a psychological evalua- 
tion does not mean that the physician is questioning the 
validity of their complaint. Even when an organic cause for 
a patient's pain can be found, it is still wise to look for other 
factors. For example, a cancer patient with painful bony 
metastases may have additional pain due to nerve damage 
and may also be depressed. Optimal therapy requires that 
each of these factors be looked for and treated. 



47 



"x 



Treatment: 
CHRONIC PAIN 



Once the evaluation process has been completed and 
the likely causative and exacerbating factors identified, 
an explicit treatment plan should be developed. An 
important part of this process is to identify specific and 
realistic functional goals for therapy, such as getting a 
good night's sleep, being able to go shopping, or return- 
ing to work. A multidisciplinary approach that utilizes 
medications, counseling, physical therapy, nerve blocks, 
and even surgery may be required to improve the 
patient's quality of life. There are also some newer, rela- 
tively invasive procedures that can be helpful for some 
patients with intractable pain. These procedures include 
implanting intraspinal cannulae to deliver morphine or 
intraspinal electrodes for spinal stimulation. There are 
no set criteria for predicting which patients will respond 



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to these procedures. They are generally reserved for 
patients who have not responded to conventional phar- 
macologic approaches. Referral to a multidisciplinary 
pain clinic for a full evaluation should precede any inva- 
sive procedures. Such referrals are clearly not necessary 
for all chronic pain patients. For some, pharmacologic 
management alone can provide adequate relief. 

ANTIDEPRESSANT MEDICATIONS The tricyclic 
anti- depressants [amitriptyline, imipramine, nortripty- 
line, desipramine (TCAs; Table 5-1)] are extremely useful 
for the management of patients with chronic pain. 
Although developed for the treatment of depression, the 
tricyclics have a spectrum of dose-related biologic activi- 
ties that include the production of analgesia in a variety 
of clinical conditions. Although the mechanism is 
unknown, the analgesic effect of TCAs has a more rapid 
onset and occurs at a lower dose than is typically 
required for the treatment of depression. Furthermore, 
patients with chronic pain who are not depressed obtain 
pain relief with antidepressants. There is evidence that 
tricyclic drugs potentiate opioid analgesia, so they may 
be useful adjuncts for the treatment of severe persistent 
pain such as occurs with malignant tumors. Table 5-2 
lists some of the painful conditions that respond to tri- 
cyclics. TCAs are of particular value in the management 
of neuropathic pain such as occurs in diabetic neuropa- 
thy and postherpetic neuralgia, for which there are few 
other therapeutic options. 

The TCAs that have been shown to relieve pain have 
significant side effects (Table 5-1; Chap. 49). Some of 
these side effects, such as orthostatic hypotension, 
drowsiness, cardiac conduction delay, memory impair- 
ment, constipation, and urinary retention, are particu- 
larly problematic in elderly patients, and several are 
additive to the side effects of opioid analgesics. The 
serotonin-selective reuptake inhibitors such as fluoxe- 
tine (Prozac) have fewer and less serious side effects 
than TCAs, but they are much less effective for relieving 
pain. It is of interest that venlafaxine (Effexor) and dulox- 
etine (Cymbalta), which are nontricyclic antidepressants 



TABLE 5-2 



PAINFUL CONDITIONS THAT RESPOND TO 
TRICYCLIC ANTIDEPRESSANTS 



Postherpetic neuralgia 3 
Diabetic neuropathy 3 
Tension headache 3 
Migraine headache 3 
Rheumatoid arthritis 3 '" 
Chronic low back pain" 
Cancer 
Central post-stroke pain 



Controlled trials demonstrate analgesia. 
^Controlled studies indicate benefit but not analgesia. 



that block both serotonin and norepinephrine reuptake, 
appear to retain most of the pain-relieving effect of 
TCAs with a side-effect profile more like that of the sero- 
tonin-selective reuptake inhibitors. These drugs may be 
particularly useful in patients who cannot tolerate the 
side effects of tricyclics. 

ANTICONVULSANTS AND ANTIARRHYTH- 
MICS These drugs are useful primarily for patients 
with neuropathic pain. Phenytoin (Dilantin) and carba- 
mazepine (Tegretol) were first shown to relieve the pain 
of trigeminal neuralgia. This pain has a characteristic 
brief, shooting, electric shock-like quality. In fact, anti- 
convulsants seem to be helpful largely for pains that 
have such a lancinating quality. Newer anticonvulsants, 
gabapentin (Neurontin) and pregabalin (Lyrica), are 
effective for a broad range of neuropathic pains. 

Antiarrhythmic drugs such as low-dose lidocaine and 
mexiletine (Mexitil) can also be effective for neuropathic 
pain. These drugs block the spontaneous activity of 
damaged primary afferent nociceptors. 

CHRONIC OPIOID MEDICATION The long- 
term use of opioids is accepted for patients with pain 
due to malignant disease. Although opioid use for 
chronic pain of nonmalignant origin is controversial, it is 
clear that for many such patients opioid analgesics are 
the best available option. This is understandable since 
opioids are the most potent and have the broadest 
range of efficacy of any analgesic medications. 
Although addiction is rare in patients who first use opi- 
oids for pain relief, some degree of tolerance and physi- 
cal dependence are likely with long-term use. Therefore, 
before embarking on opioid therapy, other options 
should be explored, and the limitations and risks of opi- 
oids should be explained to the patient. It is also impor- 
tant to point out that some opioid analgesic medica- 
tions have mixed agonist-antagonist properties (e.g., 
pentazocine and butorphanol). From a practical stand- 
point, this means that they may worsen pain by induc- 
ing an abstinence syndrome in patients who are physi- 
cally dependent on other opioid analgesics. 

With long-term outpatient use of orally administered 
opioids, it is desirable to use long-acting compounds such 
as levorphanol, methadone, or sustained-release mor- 
phine (Table 5-1). Transdermal fentanyl is another excel- 
lent option. The pharmacokinetic profile of these drug 
preparations enables prolonged pain relief, minimizes 
side effects such as sedation that are associated with high 
peak plasma levels, and reduces the likelihood of rebound 
pain associated with a rapid fall in plasma opioid concen- 
tration. Constipation is a virtually universal side effect of 
opioid use and should be treated expectantly. 

TREATMENT OF NEUROPATHIC PAIN It is 

important to individualize treatment for patients with 



neuropathic pain. Several general principles should 
guide therapy: the first is to move quickly to provide 
relief; a second is to minimize drug side effects. For 
example, in patients with postherpetic neuralgia and 
significant cutaneous hypersensitivity, topical lidocaine 
(Lidoderm patches) can provide immediate relief with- 
out side effects. Anticonvulsants (gabapentin or prega- 
balin, see earlier) or antidepressants can be used as first- 
line drugs for patients with neuropathic pain. 
Antiarrhythmic drugs such as lidocaine and mexiletene 
can be effective (see earlier). There is no consensus on 
which class of drug should be used as a first-line treat- 
ment for any chronically painful condition. However, 
because relatively high doses of anticonvulsants are 
required for pain relief, sedation is very common. Seda- 
tion is also a problem with the tricyclic antidepressants 
but is much less of a problem with serotonin/norepi- 
nephrine reuptake inhibitors (SNRIs, e.g., venlafaxine 
and duloxetine).Thus, in the elderly or in those patients 
whose daily activities require high-level mental activity, 
these drugs should be considered as the first line. In 
contrast, opioid medications should be used as a second- 
or third-line drug class. While highly effective for many 
painful conditions, opioids are sedating, and their effect 
tends to lessen over time, leading to dose escalation 
and, occasionally, a worsening of pain due to physical 



dependence. Drugs of different classes can be used in 
combination to optimize pain control. 

It is worth emphasizing that many patients, espe- 
cially those with chronic pain, seek medical attention 
primarily because they are suffering and because only 
physicians can provide the medications required for 
pain relief. A primary responsibility of all physicians is to 
minimize the physical and emotional discomfort of their 
patients. Familiarity with pain mechanisms and anal- 
gesic medications is an important step toward accom- 
plishing this aim. 



FURTHER READINGS 

CRAIG AD: How do you feel? Interoception: The sense of the 
physiological condition of the body. Nat Rev Neurosci 8:655, 
2002 

FIELDS HL: Should we be reluctant to prescribe opioids for chronic 
nonmalignant pain? Pain 129:233, 2007 

KELTNER JR. et al: Isolating the modulatory effect of expectation on 
pain transmission: A functional magnetic resonance imaging 
study. J Neurosci 26:4437, 2006 

MACINTYRE PE: Safety and efficacy of patient-controlled analgesia. 
BrJAnaesth 87:36, 2001 

WAGER TD et al: Placebo-induced changes in FMRI in the anticipa- 
tion and experience of pain. Science 303:1162, 2004 



49 



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Peter J. Goadsby ■ Neil H. Raskin 



General Principles 50 

Anatomy and Physiology of Headache 50 

Clinical Evaluation of Acute, New-Onset Headache 51 

Secondary Headache 51 

Meningitis 51 

Intracranial Hemorrhage 51 

Brain Tumor 52 

Temporal Arteritis 52 

Glaucoma 52 



Primary Headache Syndromes 52 

Migraine Headache 52 

Tension-Type Headache 59 

Trigeminal Autonomic Cephalalgias, Including Cluster 

Headache 61 

Chronic Daily Headache 63 

Other Primary Headaches 67 

Further Readings 69 



Headache is among the most common reasons that patients 
seek medical attention. Diagnosis and management is based 
on a careful clinical approach that is augmented by an 
understanding of the anatomy, physiology and pharma- 
cology of the nervous system pathways that mediate the 
various headache syndromes. 

GENERAL PRINCIPLES 

A classification system developed by the International 
Headache Society characterizes headache as primary or 
secondary (Table 6-1). Primary headaches are those in 
which headache and its associated features are the disor- 
der in itself, whereas secondary headaches are those caused 
by exogenous disorders. Primary headache often results 
in considerable disability and a decrease in the patient's 
quality of life. Mild secondary headache, such as that 
seen in association with upper respiratory tract infec- 
tions, is common but rarely worrisome. Life -threatening 
headache is relatively uncommon, but vigilance is required 
in order to recognize and appropriately treat patients with 
this category of head pain. 

ANATOMY AND PHYSIOLOGY OF HEADACHE 

Pain usually occurs when peripheral nociceptors are stim- 
ulated in response to tissue injury, visceral distension, or 



50 



other factors (Chap. 5). In such situations, pain perception 
is a normal physiologic response mediated by a healthy 
nervous system. Pain can also result when pain-producing 
pathways of the peripheral or central nervous system 
(CNS) are damaged or activated inappropriately. Headache 
may originate from either or both mechanisms. Relatively 
few cranial structures are pain-producing; these include 
the scalp, middle meningeal artery, dural sinuses, fafx cere- 
bri, and proximal segments of the large pial arteries. The 
ventricular ependyma, choroid plexus, pial veins, and 
much of the brain parenchyma are not pain-producing. 

The key structures involved in primary headache appear 
to be 

• the large intracranial vessels and dura mater 

• the peripheral terminals of the trigeminal nerve that 
innervate these structures 

• the caudal portion of the trigeminal nucleus, which extends 
into the dorsal horns of the upper cervical spinal cord and 
receives input from the first and second cervical nerve roots 
(the trigeminocervical complex) 

• the pain modulatory systems in the brain that receive 
input from trigeminal nociceptors 

The innervation of the large intracranial vessels and 
dura mater by the trigeminal nerve is known as the trigemi- 
novasadar system. Autonomic symptoms, such as lacrimation 



TABLE 6-1 



COMMON CAUSES OF HEADACHE 



PRIMARY HEADACHE 



SECONDARY HEADACHE 



TYPE 


% 


TYPE 


% 


Migraine 


16 


Systemic infection 


63 


Tension-type 


69 


Head injury 


4 


Cluster 


0.1 


Vascular disorders 


1 


Idiopathic 


2 


Subarachnoid 


<1 


stabbing 




hemorrhage 




Exertional 


1 


Brain tumor 


0.1 



Source: After J Olesen et al: The Headaches. Philadelphia, Lippincott, 
Williams &Wilkins, 2005. 



and nasal congestion, are prominent in the trigeminal auto- 
nomic cephalalgias, including cluster headache and parox- 
ysmal hemicrania, and may also be seen in migraine. These 
autonomic symptoms reflect activation of cranial parasym- 
pathetic pathways, and functional imaging studies indicate 
that vascular changes in migraine and cluster headache, 
when present, are similarly driven by these cranial auto- 
nomic systems. Migraine and other primary headache 
types are not "vascular headaches"; these disorders do not 
reliably manifest vascular changes, and treatment outcomes 
cannot be predicted by vascular effects. 

CLINICAL EVALUATION OF ACUTE, 
NEW-ONSET HEADACHE 

The patient who presents -with a new, severe headache 
has a differential diagnosis that is quite different from the 
patient with recurrent headaches over many years. In 
new-onset and severe headache, the probability of find- 
ing a potentially serious cause is considerably greater 
than in recurrent headache. Patients with recent onset of 
pain require prompt evaluation and often treatment. 
Serious causes to be considered include meningitis, sub- 
arachnoid hemorrhage, epidural or subdural hematoma, 
glaucoma, and purulent sinusitis. When worrisome 
symptoms and signs are present (Table 6-2), rapid diag- 
nosis and management is critical. 

A complete neurologic examination is an essential first 
step in the evaluation. In most cases, patients with an abnor- 
mal examination or a history of recent-onset headache 
should be evaluated by a CT or MRI study. As an initial 
screening procedure for intracranial pathology in this set- 
ting, CT and MRI methods appear to be equally sensitive. 
In some circumstances a lumbar puncture (LP) is also 
required, unless a benign etiology can be otherwise estab- 
lished. A general evaluation of acute headache might include 
the investigation of cardiovascular and renal status by blood 
pressure monitoring and urine examination; eyes by fun- 
doscopy, intraocular pressure measurement, and refraction; 
cranial arteries by palpation; and cervical spine by the effect 
of passive movement of the head and by imaging. 



TABLE 6-2 5-] 



HEADACHE SYMPTOMS THAT SUGGEST A SERIOUS 
UNDERLYING DISORDER 



"Worst" headache ever 

First severe headache 

Subacute worsening over days or weeks 

Abnormal neurologic examination 

Fever or unexplained systemic signs 

Vomiting that precedes headache 

Pain induced by bending, lifting, cough 

Pain that disturbs sleep or presents immediately upon 

awakening 

Known systemic illness 
Onset after age 55 
Pain associated with local tenderness, e.g., region of 

temporal artery 



The psychological state of the patient should also be 
evaluated since a relationship exists between head pain 
and depression. Many patients in chronic daily pain cycles 
become depressed, although depression itself is rarely a 
cause of headache. Drugs with antidepressant actions are 
also effective in the prophylactic treatment of both 
tension-type headache and migraine. 

Underlying recurrent headache disorders may be acti- 
vated by pain that follows otologic or endodontic surgi- 
cal procedures. Thus, pain about the head as the result of 
diseased tissue or trauma may reawaken an otherwise qui- 
escent migrainous syndrome. Treatment of the headache 
is largely ineffective until the cause of the primary prob- 
lem is addressed. 

Serious underlying conditions that are associated with 
headache are described below. Brain tumor is a rare cause 
of headache and even less commonly a cause of severe 
pain. The vast majority of patients presenting with severe 
headache have a benign cause. 



SECONDARY HEADACHE 

The management of secondary headache focuses on 
diagnosis and treatment of the underlying condition. 

MENINGITIS 

Acute, severe headache with stiff neck and fever suggests 
meningitis. LP is mandatory. Often there is striking accen- 
tuation of pain with eye movement. Meningitis can be 
easily mistaken for migraine in that the cardinal symptoms 
of pounding headache, photophobia, nausea, and vomiting 
are present. Meningitis is discussed in Chaps. 35 and 36. 

INTRACRANIAL HEMORRHAGE 

Acute, severe headache with stiff neck but without fever 
suggests subarachnoid hemorrhage. A ruptured aneurysm, 



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arteriovenous malformation, or intraparenchymal hem- 
orrhage may also present with headache alone. Rarely, if 
the hemorrhage is small or below the foramen magnum, 
the head CT scan can be normal. Therefore, LP may be 
required to definitively diagnose subarachnoid hemorrhage. 
Intraparenchymal hemorrhage is discussed in Chap. 21 and 
subarachnoid hemorrhage in Chap. 22. 

BRAIN TUMOR 

Approximately 30% of patients with brain tumors consider 
headache to be their chief complaint. The head pain is 
usually nondescript — an intermittent deep, dull aching of 
moderate intensity, which may worsen with exertion or 
change in position and may be associated with nausea and 
vomiting. This pattern of symptoms results from migraine 
far more often than from brain tumor. The headache of 
brain tumor disturbs sleep in about 10% of patients. Vomit- 
ing that precedes the appearance of headache by weeks is 
highly characteristic of posterior fossa brain tumors. A his- 
tory of amenorrhea or galactorrhea should lead one to 
question whether a prolactin-secreting pituitary adenoma 
(or the polycystic ovary syndrome) is the source of 
headache. Headache arising de novo in a patient with 
known malignancy suggests either cerebral metastases or 
carcinomatous meningitis, or both. Head pain appearing 
abruptly after bending, lifting, or coughing can be due to a 
posterior fossa mass (or a Chiari malformation). Brain 
tumors are discussed in Chap. 32. 

TEMPORAL ARTERITIS 

Temporal (giant cell) arteritis is an inflammatory disorder 
of arteries that frequently involves the extracranial carotid 
circulation. It is a common disorder of the elderly; its annual 
incidence is 77 per 100,000 individuals aged 50 years and 
older. The average age of onset is 70 years, and women 
account for 65% of cases. About half of patients with 
untreated temporal arteritis develop blindness due to 
involvement of the ophthalmic artery and its branches; 
indeed, the ischemic optic neuropathy induced by giant 
cell arteritis is the major cause of rapidly developing bilat- 
eral blindness in patients >60 years. Because treatment 
with glucocorticoids is effective in preventing this com- 
plication, prompt recognition of the disorder is important. 
Typical presenting symptoms include headache, poly- 
myalgia rheumatica, jaw claudication, fever, and weight 
loss. Headache is the dominant symptom and often 
appears in association with malaise and muscle aches. 
Head pain may be unilateral or bilateral and is located 
temporally in 50% of patients but may involve any and 
all aspects of the cranium. Pain usually appears gradually 
over a few hours before peak intensity is reached; occa- 
sionally, it is explosive in onset. The quality of pain is 
only seldom throbbing; it is almost invariably described 
as dull and boring, with superimposed episodic stabbing 
pains similar to the sharp pains that appear in migraine. 



Most patients can recognize that the origin of their head 
pain is superficial, external to the skull, rather than 
originating deep within the cranium (the pain site for 
migraineurs) . Scalp tenderness is present, often to a 
marked degree; brushing the hair or resting the head on 
a pillow may be impossible because of pain. Headache is 
usually worse at night and often aggravated by exposure 
to cold. Additional findings may include reddened, ten- 
der nodules or red streaking of the skin overlying the 
temporal arteries, and tenderness of the temporal or, less 
commonly, the occipital arteries. 

The erythrocyte sedimentation rate (ESR) is often, 
though not always, elevated; a normal ESR does not 
exclude giant cell arteritis. A temporal artery biopsy fol- 
lowed by treatment with prednisone 80 mg daily for the 
first 4—6 weeks should be initiated when clinical suspi- 
cion is high. The prevalence of migraine among the 
elderly is substantial, considerably higher than that of 
giant cell arteritis. Migraineurs often report amelioration 
of their headaches with prednisone; thus, caution must 
be used when interpreting the therapeutic response. 

GLAUCOMA 

Glaucoma may present with a prostrating headache asso- 
ciated with nausea and vomiting. The headache often 
starts with severe eye pain. On physical examination, the 
eye is often red with a fixed, moderately dilated pupil. 
Glaucoma is discussed in Chap. 17. 

PRIMARY HEADACHE SYNDROMES 

Primary headaches are disorders in which headache and 
associated features occur in the absence of any exoge- 
nous cause (Table 6-1). The most common are migraine, 
tension-type headache, and cluster headache. 

MIGRAINE HEADACHE 

Migraine, the second most common cause of headache, 
afflicts approximately 15% of women and 6% of men. It 
is usually an episodic headache that is associated with 
certain features such as sensitivity to light, sound, or 
movement; nausea and vomiting often accompany the 
headache. A useful description of migraine is a benign 
and recurring syndrome of headache associated with 
other symptoms of neurologic dysfunction in varying 
admixtures (Table 6-3). Migraine can often be recog- 
nized by its activators, referred to as triggers. 

The brain of the migraineur is particularly sensitive 
to environmental and sensory stimuli; migraine -prone 
patients do not habituate easily to sensory stimuli. This 
sensitivity is amplified in females during the menstrual 
cycle. Headache can be initiated or amplified by various 
triggers, including glare, bright lights, sounds, or other 
afferent stimulation; hunger; excess stress; physical 



TABLE 6-3 



SYMPTOMS ACCOMPANYING SEVERE MIGRAINE 
ATTACKS IN 500 PATIENTS 



SYMPTOM 


PATIENTS AFFECTED, % 


Nausea 


87 


Photophobia 


82 


Lightheadedness 


72 


Scalp tenderness 


65 


Vomiting 


56 


Visual disturbances 


36 


Photopsia 


26 


Fortification spectra 


10 


Paresthesias 


33 


Vertigo 


33 


Alteration of consciousness 


18 


Syncope 


10 


Seizure 


4 


Confusional state 


4 


Diarrhea 


16 



Source: From NH Raskin, Headache, 2d ed. 
Livingston, 1988; with permission. 



New York, Churchill 



exertion; stormy weather or barometric pressure changes; 
hormonal fluctuations during menses; lack of or excess 
sleep; and alcohol or other chemical stimulation. Knowl- 
edge of a patient's susceptibility to specific triggers can 



be useful in management strategies involving lifestyle 53 
adjustments. 

Pathogenesis 

The sensory sensitivity that is characteristic of migraine 
is probably due to dysfunction of monoaminergic sen- 
sory control systems located in the brainstem and thala- 
mus (Fig. 6-1). 

Activation of cells in the trigeminal nucleus results in 
the release of vasoactive neuropeptides, particularly cal- 
citonin gene-related peptide (CGRP), at vascular termi- 
nations of the trigeminal nerve. Recently, antagonists of 
CGRP have shown some early promise in the therapy 
of migraine. Centrally, the second-order trigeminal neu- 
rons cross the midline and project to ventrobasal and 
posterior nuclei of the thalamus for further processing. 
Additionally, there are projections to the periaqueductal 
gray and hypothalamus, from which reciprocal descending 
systems have established anti-nociceptive effects. Other 
brainstem regions likely to be involved in descending 
modulation of trigeminal pain include the nucleus locus 
coeruleus in the pons and the rostroventromedial medulla. 

Pharmacologic and other data point to the involvement 
of the neurotransmitter 5-hydroxytryptamine (5-HT; also 
known as serotonin) in migraine. Approximately 50 years 
ago, methysergide was found to antagonize certain peripheral 



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salivatoiy nucleus 




FIGURE 6-1 

Brainstem pathways that modulate sensory input. The 

key pathway for pain in migraine is the trigeminovascular 
input from the meningeal vessels, which passes through the 
trigeminal ganglion and synapses on second-order neurons 
in the trigeminocervical complex. These neurons in turn 



Pterygopalatine 
ganglion 



project in the quintothalamic tract and, after decussating in 
the brainstem, synapse on neurons in the thalamus. Impor- 
tant modulation of the trigeminovascular nociceptive input 
comes from the dorsal raphe nucleus, locus coeruleus, and 
nucleus raphe magnus. 



54 



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A B 

FIGURE 6-2 

Positron emission tomography (PET) activation in migraine. 

In spontaneous attacks of episodic migraine (A) there is activa- 
tion of the region of the dorsolateral pons (intersection of dark 
blue lines); an identical pattern is found in chronic migraine (not 
shown). This area, which includes the noradrenergic locus 
coeruleus, is fundamental to the expression of migraine. 



Moreover, lateralization of changes in this region of the brain- 
stem correlates with lateralization of the head pain in hemicra- 
nial migraine; the scans shown in panels B and C are of 
patients with acute migraine headache on the right and left 
side, respectively. (From S Afridi et al: Arch Neurol 62:1270, 
2005; Brain 128:932, 2005.) 



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actions of 5-HT and was introduced as the first drug 
capable of preventing migraine attacks. The triptans are 
designed to selectively stimulate subpopulations of 
5-HT receptors; at least 14 different 5-HT receptors exist 
in humans. The triptans are potent agonists of 5-HT 1B , 
5-HT 1D , and 5-HT 1F receptors and are less potent at the 
5-HT 1A receptor. A growing body of data indicates that 
the antimigraine efficacy of the triptans relates to their 
ability to stimulate 5-HT 1B/1D receptors, which are located 
on both blood vessels and nerve terminals. 

Data also support a role for dopamine in the patho- 
physiology of certain subtypes of migraine. Most migraine 
symptoms can be induced by dopaminergic stimulation. 
Moreover, there is dopamine receptor hypersensitivity in 
migraineurs, as demonstrated by the induction of yawn- 
ing, nausea, vomiting, hypotension, and other symptoms 
of a migraine attack by dopaminergic agonists at doses 
that do not affect nonmigraineurs. Dopamine receptor 
antagonists are effective therapeutic agents in migraine, 
especially when given parenteralfy or concurrently with 
other antimigraine agents. 

Migraine genes identified by studying families with 
familial hemiplegic migraine (FHM) reveal involvement 
of ion channels, suggesting that alterations in membrane 
excitability can predispose to migraine. Mutations involv- 
ing the Ca v 2.1 (P/Q) type voltage-gated calcium chan- 
nel CACNA 1A gene are now known to cause FHM 1 ; 
this mutation is responsible for about 50% of FHM. 
Mutations in the Na + -K + ATPase ATP1A2 gene, designated 



FHM 2, are responsible for about 20% of FHM. Muta- 
tions in the neuronal voltage-gated sodium channel 
SCN1A cause FHM 3. Functional neuroimaging has 
suggested that brainstem regions in migraine (Fig. 6-2) 
and the posterior hypothalamic gray matter region close 
to the human circadian pacemaker cells of the suprachi- 
asmatic nucleus in cluster headache (Fig. 6-3) are good 
candidates for specific involvement in primary headache. 




FIGURE 6-3 

Posterior hypothalamic gray matter activation on positron 
emission tomography (PET) in a patient with acute cluster 
headache. (From A May et al: Lancet 352:275, 1998.) 



TABLE 6-4 



SIMPLIFIED DIAGNOSTIC CRITERIA FOR MIGRAINE 



Repeated attacks of headache lasting 4-72 h in patients 
with a normal physical examination, no other reasonable 
cause for the headache, and: 

At least 2 of the following 



features: 

Unilateral pain 
Throbbing pain 

Aggravation by movement 
Moderate or severe intensity 



Plus at least 1 of the 
following features: 

Nausea/vomiting 
Photophobia and 
phonophobia 



Source: Adapted from the International Headache Society Classifi- 
cation (Headache Classification Committee of the International 
Headache Society, 2004). 



Diagnosis and Clinical Features 

Diagnostic criteria for migraine headache are listed in 
Table 6-4. A high index of suspicion is required to diag- 
nose migraine: the migraine aura, consisting of visual dis- 
turbances with flashing lights or zigzag lines moving across 
the visual field or of other neurologic symptoms, is 
reported in only 20—25% of patients. A headache diary can 
often be helpful in making the diagnosis; this is also helpful 
in assessing disability and the frequency of treatment for 
acute attacks. Patients with episodes of migraine that 
occur daily or near-daily are considered to have chronic 



migraine (see Chronic Daily Headache, below). Migraine 
must be differentiated from tension-type headache (dis- 
cussed below), the most common primary headache syn- 
drome seen in clinical practice. Migraine at its most basic level 
is headache with associated features, and tension-type headache is 
headache that is featureless. Most patients with disabling headache 
probably have migraine. 

Patients with acephalgic migraine experience recur- 
rent neurologic symptoms, often with nausea or vomit- 
ing, but with little or no headache. Vertigo can be promi- 
nent; it has been estimated that one-third of patients 
referred for vertigo or dizziness have a primary diagnosis 
of migraine. 



55 



"k 



Treatment: 

MIGRAINE HEADACHES 



Once a diagnosis of migraine has been established, it is 
important to assess the extent of a patient's disease and 
disability. The Migraine Disability Assessment Score (MIDAS) 
is a well-validated, easy-to-use tool (Fig. 6-4). 

Patient education is an important aspect of migraine 
management. Information for patients is available at 
www.achenet.org, the website of the American Council 
for Headache Education (ACHE). It is helpful for patients 
to understand that migraine is an inherited tendency to 
headache; that migraine can be modified and con- 
trolled by lifestyle adjustments and medications, but it 
cannot be eradicated; and that, except in some occasions 



CD 
QJ 



*MIDAS Questionnaire 

INSTRUCTIONS: Please answer the following questions about ALL headaches you have had 
over the last 3 months. Write zero if you did not do the activity in the last 3 months. 

1 . On how many days in the last 3 months did you miss work or school because 

of your headaches? days 

2. How many days in the last 3 months was your productivity at work or school 
reduced by half or more because of your headaches (do not include days 

you counted in question 1 where you missed work or school)? days 

3. On how many days in the last 3 months did you not do household work 

because of your headaches? days 

4. How many days in the last 3 months was your productivity in household work 
reduced by half or more because of your headaches (do not include days 

you counted in question 3 where you did not do household work) 1 ? days 

5. On how many days in the last 3 months did you miss family, social, or leisure 

activities because of your headaches? days 

A. On how many days in the last 3 months did you have a headache? (If a 

headache lasted more than one day, count each day.) days 

B. On a scale of 0-10, on average how painful were these headaches? (Where 

= no pain at all, and 10 = pain as bad as it can be.) 

'Migraine Disability Assessment Score 

(Questions 1-5 are used to calculate the MIDAS score.) 

Grade I — Minimal or Infrequent Disability: 0-5 

Grade II — Mild or Infrequent Disability: 6-10 

Grade III— Moderate Disability: 11-20 

Grade IV— Severe Disability: > 20 

FIGURE 6-4 

MIDAS Questionnaire. (From Innovative Medical Research 1997.) 



56 



a> 

5T 

o' 



o 



a> 



in women on oral estrogens or contraceptives, migraine 
is not associated with serious or life-threatening ill- 
nesses. Recent studies have demonstrated an increased 
number of cerebellar white matter lesions of uncertain 
significance in those with migraine with aura. 

Nonpharmacologic Management Migraine 
can often be managed to some degree by a variety of 
nonpharmacologic approaches. Most patients benefit 
by the identification and avoidance of specific headache 
triggers. A regulated lifestyle is helpful, including a 
healthful diet, regular exercise, regular sleep patterns, 
avoidance of excess caffeine and alcohol, and avoidance 
of acute changes in stress levels. 

The measures that benefit a given individual should 
be used routinely since they provide a simple, cost- 
effective approach to migraine management. Patients 
with migraine do not encounter more stress than 
headache-free individuals; overresponsiveness to stress 
appears to be the issue. Since the stresses of everyday 
living cannot be eliminated, lessening one's response to 
stress by various techniques is helpful for many 
patients. These may include yoga, transcendental medi- 
tation, hypnosis, and conditioning techniques such as 
biofeedback. For most patients, this approach is, at best, 
an adjunct to pharmacotherapy. Nonpharmacologic 
measures are unlikely to prevent all migraine attacks. 
When these measures fail to prevent an attack, pharma- 
cologic approaches are then needed to abort an attack. 

Acute Attack Therapies for Migraine The 

mainstay of pharmacologic therapy is the judicious use 
of one or more of the many drugs that are effective in 
migraine (Table 6-5). The selection of the optimal regi- 
men for a given patient depends on a number of factors, 
the most important of which is the severity of the 
attack. Mild migraine attacks can usually be managed by 
oral agents; the average efficacy rate is 50-70%. Severe 
migraine attacks may require parenteral therapy. Most 
drugs effective in the treatment of migraine are mem- 
bers of one of three major pharmacologic classes: anti- 
inflammatory agents, 5HT 1B/1D receptor agonists, and 
dopamine receptor antagonists. 

In general, an adequate dose of whichever agent is 
chosen should be used as soon as possible after the 
onset of an attack. If additional medication is required 
within 60 min because symptoms return or have not 
abated, the initial dose should be increased for subse- 
quent attacks. Migraine therapy must be individualized; 
a standard approach for all patients is not possible. A 
therapeutic regimen may need to be constantly refined 
until one is identified that provides the patient with 
rapid, complete, and consistent relief with minimal side 
effects (Table 6-6). 

Nonsteroidal Anti- Inflammatory Drugs 
(NSAIDs) Both the severity and duration of a migraine 



attack can be reduced significantly by anti-inflammatory 
agents (Table 6-5). Indeed, many undiagnosed migraineurs 
are self-treated with nonprescription NSAIDs. A general 
consensus is that NSAIDs are most effective when taken 
early in the migraine attack. However, the effectiveness of 
anti-inflammatory agents in migraine is usually less than 
optimal in moderate or severe migraine attacks. The com- 
bination of acetaminophen, aspirin, and caffeine has been 
approved for use by the U.S. Food and Drug Administration 
(FDA) for the treatment of mild to moderate migraine. The 
combination of aspirin and metoclopramide has been 
shown to be equivalent to a single dose of sumatriptan. 
Important side effects of NSAIDs include dyspepsia and 
gastrointestinal irritation. 

5-HT-i Agonists 

Oral Stimulation of 5-HT lB/1D receptors can stop an 
acute migraine attack. Ergotamine and dihydroergota- 
mine are nonselective receptor agonists, while the trip- 
tans are selective 5-HT 1B/1D receptor agonists. A variety 
of triptans (e.g., naratriptan, rizatriptan, eletriptan, suma- 
triptan, zolmitriptan, almotriptan, frovatriptan) are now 
available for the treatment of migraine. 

Each drug in the triptan class has similar pharmaco- 
logic properties but varies slightly in terms of clinical 
efficacy. Rizatriptan and eletriptan are the most effica- 
cious of the triptans currently available in the United 
States. Sumatriptan and zolmitriptan have similar rates 
of efficacy as well as time to onset, whereas naratriptan 
and frovatriptan are the slowest-acting and least effica- 
cious. Clinical efficacy appears to be related more to 
the f max (time to peak plasma level) than to the potency, 
half-life, or bioavailability. This observation is consistent 
with a large body of data indicating that faster-acting 
analgesics are more effective than slower-acting agents. 

Unfortunately, monotherapy with a selective oral 5- 
HT 1B/1D agonist does not result in rapid, consistent, and 
complete relief of migraine in all patients. Triptans are 
not effective in migraine with aura unless given after 
the aura is completed and the headache initiated. Side 
effects are common though often mild and transient. 
Moreover, 5-HT 1B/lD agonists are contraindicated in indi- 
viduals with a history of cardiovascular and cerebrovas- 
cular disease. Recurrence of headache is another impor- 
tant limitation of triptan use and occurs at least 
occasionally in most patients. 

Ergotamine preparations offer a nonselective means 
of stimulating 5-HT, receptors. A nonnauseating dose of 
ergotamine should be sought since a dose that pro- 
vokes nausea is too high and may intensify head pain. 
Except for a sublingual formulation of ergotamine, oral 
formulations of ergotamine also contain 100 mg caf- 
feine (theoretically to enhance ergotamine absorption 
and possibly to add additional analgesic activity). The 
average oral ergotamine dose for a migraine attack is 2 mg. 
Since the clinical studies demonstrating the efficacy of 



TABLE 6-5 



TREATMENT OF ACUTE MIGRAINE 



57 



DRUG 




TRADE NAME 


DOSAGE 


Simple Analgesics 


Acetaminophen, aspirin, 


Excedrin Migraine 


Two tablets or caplets q6h (max 8 per day) 


caffeine 








NSAIDs 








Naproxen 




Aleve, Anaprox, generic 


220-550 mg PO bid 


Ibuprofen 




Advil, Motrin, Nuprin, 
generic 


400 mg PO q3-4h 


Tolfenamic acid 




Clotam Rapid 


200 mg PO. May repeat x 1 after 1-2 h 


5-HT! Agonists 








Oral 








Ergotamine 




Ergomar 


One 2 mg sublingual tablet at onset and q 1 / 2 h (max 3 per day, 
5 per week) 


Ergotamine 1 mg, 




Ercaf, Wigraine 


One or two tablets at onset, then one tablet q 1 / 2 h 


caffeine 100 mg 






(max 6 per day,1 per week) 


Naratriptan 




Amerge 


2.5 mg tablet at onset; may repeat once after 4 h 


Rizatriptan 




Maxalt 
Maxalt-MLT 


5-1 mg tablet at onset; may repeat after 2 h (max 30 mg/d) 


Sumatriptan 




Imitrex 


50-1 00 mg tablet at onset; may repeat after 2 h (max 200 mg/d) 


Frovatriptan 




Frova 


2.5 mg tablet at onset, may repeat after 2 h (max 5 mg/d) 


Almotriptan 




Axert 


12.5 mg tablet at onset, may repeat after 2 h (max 25 mg/d) 


Eletriptan 




Relpax 


40 or 80 mg 


Zolmitriptan 




Zomig 

Zomig Rapimelt 


2.5 mg tablet at onset; may repeat after 2 h (max 10 mg/d) 


Nasal 








Dihydroergotamine 




Migranal Nasal Spray 


Prior to nasal spray, the pump must be primed 4 times; 1 spray 
(0.5 mg) is administered, followed in 15 min by a second spray 


Sumatriptan 




Imitrex Nasal Spray 


5-20 mg intranasal spray as 4 sprays of 5 mg or a single 20 mg 
spray (may repeat once after 2 h, not to exceed a dose of 40 mg/d) 


Zolmitriptan 




Zomig 


5 mg intranasal spray as one spray (may repeat once after 2 h, 
not to exceed a dose of 1 mg/d) 


Parenteral 








Dihydroergotamine 




DHE-45 


1 mg IV, IM, or SC at onset and q1 h (max 3 mg/d, 6 mg per week) 


Sumatriptan 




Imitrex Injection 


6 mg SC at onset (may repeat once after 1 h for max of 2 doses 
in 24 h) 


Dopamine Antagonists 






Oral 








Metoclopramide 




Reglan, 3 generic 3 


5-1 mg/d 


Prochlorperazine 




Compazine, 3 generic 3 


1-25 mg/d 


Parenteral 








Chlorpromazine 




Generic 3 


0.1 mg/kg IV at 2 mg/min; max 35 mg/d 


Metoclopramide 




Reglan, 3 generic 


10mglV 


Prochlorperazine 




Compazine, 3 generic 3 


10mglV 


Other 








Oral 








Acetaminophen, 325 


mg, plus 


Midrin, Duradrin, generic 


Two capsules at onset followed by 1 capsule q1 h 


dichloralphenazone, 


100 mg, 




(max 5 capsules) 


plus isometheptene, 


65 mg 






Nasal 








Butorphanol 




Stadol 3 


1 mg (1 spray in 1 nostril), may repeat if necessary in 1-2 h 


Parenteral 








Narcotics 




Generic 3 


Multiple preparations and dosages; see Table 5-1 



QJ 
QJ 



a Not all drugs are specifically indicated by the FDA for migraine. Local regulations and guidelines should be consulted. 

Note: Antiemetics (e.g., domperidone 1 mg or ondansetron) or prokinetics (e.g., metoclopramide 1 mg) are sometimes useful adjuncts. 

NSAIDs, nonsteroidal anti-inflammatory drugs; 5-HT, 5-hydroxytryptamine. 



58 TABLE 6-6 



CLINICAL STRATIFICATION OF ACUTE SPECIFIC 
MIGRAINE TREATMENTS 



a> 
ST 
o' 



o 
in 



a> 



CLINICAL SITUATION 


TREATMENT OPTIONS 


Failed NSAIDS/ 


First tier 


analgesics 


Sumatriptan 50 mg or 1 00 mg PO 




Almotriptan 12.5 mg PO 




Rizatriptan 10 mg PO 




Eletriptan 40 mg PO 




Zolmitriptan 2.5 mg PO 




Slower effect/better tolerability 




Naratriptan 2.5 mg PO 




Frovatriptan 2.5 mg PO 




Infrequent headache 




Ergotamine 1-2 mg PO 




Dihydroergotamine nasal spray 




2mg 


Early nausea or 


Zolmitriptan 5 mg nasal spray 


difficulties taking 


Sumatriptan 20 mg nasal spray 


tablets 


Rizatriptan 10 mg MLT wafer 


Headache recurrence 


Ergotamine 2 mg (most effective 




PR/usually with caffeine) 




Naratriptan 2.5 mg PO 




Almotriptan 12.5 mg PO 




Eletriptan 40 mg 


Tolerating acute 


Naratriptan 2.5 mg 


treatments poorly 


Almotriptan 12.5 mg 


Early vomiting 


Zolmitriptan 5 mg nasal spray 




Sumatriptan 25 mg PR 




Sumatriptan 6 mg SC 


Menses-related 


Prevention 


headache 


Ergotamine PO at night 




Estrogen patches 




Treatment 




Triptans 




Dihydroergotamine nasal spray 


Very rapidly 


Zolmitriptan 5 mg nasal spray 


developing 


Sumatriptan 6 mg SC 


symptoms 


Dihydroergotamine 1 mg IM 



ergotamine in migraine predated the clinical trial 
methodologies used with the triptans, it is difficult to 
assess the clinical efficacy of ergotamine versus the trip- 
tans. In general, ergotamine appears to have a much 
higher incidence of nausea than triptans, but less 
headache recurrence. 

Nasal The fastest-acting nonparenteral antimigraine 
therapies that can be self-administered include nasal for- 
mulations of dihydroergotamine (Migranal), zolmitriptan 
(Zomig nasal), or sumatriptan. The nasal sprays result in 
substantial blood levels within 30-60 min. Although in 
theory nasal sprays might provide faster and more effec- 
tive relief of a migraine attack than oral formulations, 
their reported efficacy is only -50-60%. 

Parenteral Parenteral administration of drugs such 
as dihydroergotamine and sumatriptan is approved by 



the FDA for the rapid relief of a migraine attack. Peak 
plasma levels of dihydroergotamine are achieved 3 min 
after intravenous dosing, 30 min after intramuscular 
dosing, and 45 min after subcutaneous dosing. If an 
attack has not already peaked, subcutaneous or intra- 
muscular administration of 1 mg dihydroergotamine 
suffices for about 80-90% of patients. Sumatriptan, 6 mg 
subcutaneously, is effective in -70-80% of patients. 

Dopamine Antagonists 

Oral Oral dopamine antagonists should be consid- 
ered as adjunctive therapy in migraine. Drug absorption 
is impaired during migraine because of reduced gas- 
trointestinal motility. Delayed absorption occurs even in 
the absence of nausea and is related to the severity of 
the attack and not its duration. Therefore, when oral 
NSAIDs and/or triptan agents fail, the addition of a 
dopamine antagonist such as metoclopramide, 10 mg, 
should be considered to enhance gastric absorption. In 
addition, dopamine antagonists decrease nausea/vomit- 
ing and restore normal gastric motility. 

Parenteral Parenteral dopamine antagonists (e.g., 
chlorpromazine, prochlorperazine, metoclopramide) can 
also provide significant acute relief of migraine; they can 
be used in combination with parenteral 5-HT 1B/1D ago- 
nists. A common intravenous protocol used for the treat- 
ment of severe migraine is the administration over 
2 min of a mixture of 5 mg of prochlorperazine and 
0.5 mg of dihydroergotamine. 

Other Medications for Acute Migraine 
Oral The combination of acetaminophen, dichlo- 
ralphenazone, and isometheptene, one to two capsules, 
has been classified by the FDA as "possibly" effective in 
the treatment of migraine. Since the clinical studies 
demonstrating the efficacy of this combination anal- 
gesic in migraine predated the clinical trial methodolo- 
gies used with the triptans, it is difficult to compare the 
efficacy of this sympathomimetic compound to other 
agents. 

Nasal A nasal preparation of butorphanol is available 
for the treatment of acute pain. As with all narcotics, the 
use of nasal butorphanol should be limited to a select 
group of migraineurs, as described below. 

Parenteral Narcotics are effective in the acute treat- 
ment of migraine. For example, intravenous meperidine 
(50-100 mg) is given frequently in the emergency room. 
This regimen "works" in the sense that the pain of 
migraine is eliminated. However, this regimen is clearly 
suboptimal for patients with recurrent headache. Nar- 
cotics do not treat the underlying headache mecha- 
nism; rather, they act to alter the pain sensation. More- 
over, in patients taking oral narcotics such as oxycodone 
or hydrocodone, narcotic addiction can greatly confuse 



the treatment of migraine. Narcotic craving and/or with- 
drawal can aggravate and accentuate migraine. There- 
fore, it is recommended that narcotic use in migraine be 
limited to patients with severe, but infrequent, headaches 
that are unresponsive to other pharmacologic approaches. 

Medication-Overuse Headache Acute attack 
medications, particularly codeine or barbiturate- 
containing compound analgesics, have a propensity to 
aggravate headache frequency and induce a state of 
refractory daily or near-daily headache called medication- 
overuse headache.Jhis condition is likely not a separate 
headache entity but a reaction of the migraine patient 
to a particular medicine. Migraine patients who have 
two or more headache days a week should be cautioned 
about frequent analgesic use (see Chronic Daily 
Headache, below). 

Preventive Treatments for Migraine Patients 
with an increasing frequency of migraine attacks, or 
with attacks that are either unresponsive or poorly 
responsive to abortive treatments, are good candidates 
for preventive agents. In general, a preventive medica- 
tion should be considered in the subset of patients with 
five or more attacks a month. Significant side effects are 
associated with the use of many of these agents; fur- 
thermore, determination of dose can be difficult since 
the recommended doses have been derived for condi- 
tions other than migraine. The mechanism of action of 
these drugs is unclear; it seems likely that the brain sen- 
sitivity that underlies migraine is modified. Patients are 
usually started on a low dose of a chosen treatment; the 
dose is then gradually increased, up to a reasonable 
maximum to achieve clinical benefit. 

Drugs that have the capacity to stabilize migraine are 
listed in Table 6-7. Drugs must be taken daily, and there 
is usually a lag of at least 2-1 2 weeks before an effect is 
seen. The drugs that have been approved by the FDA for 
the prophylactic treatment of migraine include propra- 
nolol, timolol, sodium valproate, topiramate, and methy- 
sergide (not available in the United States). In addition, a 
number of other drugs appear to display prophylactic 
efficacy. This group includes amitriptyline, nortriptyline, 
flunarizine, phenelzine, gabapentin, topiramate, and 
cyproheptadine. Phenelzine and methysergide are usu- 
ally reserved for recalcitrant cases because of their seri- 
ous potential side effects. Phenelzine is a monoamine 
oxidase inhibitor (MAOI); therefore, tyramine-containing 
foods, decongestants, and meperidine are contraindi- 
cated. Methysergide may cause retroperitoneal or car- 
diac valvular fibrosis when it is used for >6 months, and 
thus monitoring is required for patients using this drug; 
the risk of fibrosis is about 1:1 500 and is likely to reverse 
after the drug is stopped. 

The probability of success with any one of the antimi- 
graine drugs is 50-75%. Many patients are managed 



adequately with low-dose amitriptyline, propranolol, 
topiramate, gabapentin, or valproate. If these agents fail 
or lead to unacceptable side effects, second-line agents 
such as methysergide or phenelzine can be used. Once 
effective stabilization is achieved, the drug is continued 
for 5-6 months and then slowly tapered to assess the 
continued need. Many patients are able to discontinue 
medication and experience fewer and milder attacks for 
long periods, suggesting that these drugs may alter the 
natural history of migraine. 



TENSION-TYPE HEADACHE 



59 



Clinical Features 



CD 
QJ 



The term tension-type headache (TTH) is commonly used a> 
to describe a chronic head-pain syndrome characterized ^ 
by bilateral tight, bandlike discomfort. The pain typically 
builds slowly, fluctuates in severity, and may persist more 
or less continuously for many days. The headache may 
be episodic or chronic (present >15 days per month). 

A useful clinical approach is to diagnose TTH in patients 
whose headaches are completely without accompanying 
features such as nausea, vomiting, photophobia, phono- 
phobia, osmophobia, throbbing, and aggravation with 
movement. Such an approach neatly separates migraine, 
which has one or more of these features and is the main 
differential diagnosis, from TTH. However, the Interna- 
tional Headache Society's definition of TTH allows an 
admixture of nausea, photophobia, or phonophobia in 
various combinations, illustrating the difficulties in distin- 
guishing these two clinical entities. Patients whose headaches 
fit the TTH phenotype and who have migraine at other 
times, along with a family history of migraine, migrain- 
ous illnesses of childhood, or typical migraine triggers 
to their migraine attacks, may be biologically different 
from those who have TTH headache with none of the 
features. 

Pathophysiology 

The pathophysiology of TTH is incompletely understood. 
It seems likely that TTH is due to a primary disorder of 
CNS pain modulation alone, unlike migraine, which 
involves a more generalized disturbance of sensory modu- 
lation. Data suggest a genetic contribution to TTH, but 
this may not be a valid finding: given the current diagnos- 
tic criteria, the studies undoubtedly included many 
migraine patients. The name tension-type headache implies 
that pain is a product of nervous tension, but there is no 
clear evidence for tension as an etiology. Muscle contrac- 
tion has been considered to be a feature that distinguishes 
TTH from migraine, but there appear to be no differences 
in contraction between the two headache types. 



60 



TABLE 6-7 



PREVENTIVE TREATMENTS IN MIGRAINE 3 



DRUG 



DOSE 



SELECTED SIDE EFFECTS 



Pizotifen b 



Beta blocker 



0.5-2 mg qd 



Weight gain 
Drowsiness 



Propranolol 



Tricyclics 



40-120 mg bid 



Reduced energy 
Tiredness 
Postural symptoms 
Contraindicated in asthma 





Amitriptyline 


10-75 mg at night 


Drowsiness 




Dothiepin 


25-75 mg at night 




f*l 


Nortriptyline 


25-75 mg at night 


Note: Some patients may only need a total dose of 


E5' 






10 mg, although generally 1-1 .5 mg/kg body weight is 


r->' 

QJ 






required 




Anticonvulsants 






■=> 


Topiramate 


25-200 mg/d 


Paresthesias 








Cognitive symptoms 


ST 






Weight loss 


o' 






Glaucoma 


o 






Caution with nephrolithiasis 




Valproate 


400-600 mg bid 


Drowsiness 








Weight gain 


o 






Tremor 


o~ 






Hair loss 


r-i' 






Fetal abnormalities 


O 






Hematologic or liver abnormalities 


CO 


Gabapentin 


900-3600 mg qd 


Dizziness 


ro 


Serotonergic drugs 




Sedation 




Methysergide 


1-4 mg qd 


Drowsiness 
Leg cramps 
Hair loss 

Retroperitoneal fibrosis (1 -month drug holiday is required 
every 6 months) 




Flunarizine b 


5-15 mg qd 


Drowsiness 
Weight gain 
Depression 
Parkinsonism 




No convincing evidence from controlled trials 




Verapamil 








Controlled trials demonstrate no effect 






Nimodipine 








Clonidine 








SSRIs: fluoxetine 







s Commonly used preventives are listed with reasonable doses and common side effects. Not all listed medicines are 
approved by the FDA; local regulations and guidelines should be consulted. 
b Not available in the United States. 



Be 



Treatment: 
TENSION-TYPE HEADACHE 



The pain of TTH can generally be managed with simple 
analgesics such as acetaminophen, aspirin, or NSAIDs. 
Behavioral approaches including relaxation can also be 
effective. Clinical studies have demonstrated that triptans 
in pure TTH are not helpful, although triptans are effective 
in TTH when the patient also has migraine. For chronic 
TTH,amitriptyline is the only proven treatment (Table 6-7); 
other tricyclics, selective serotonin reuptake inhibitors, and 
the benzodiazepines have not been shown to be effective. 
There is no evidence for the efficacy of acupuncture. 
Placebo controlled trials of botulinum toxin type A in 
chronic TTH have not shown benefit. 

TRIGEMINAL AUTONOMIC CEPHALALGIAS, 
INCLUDING CLUSTER HEADACHE 

The trigeminal autonomic cephalalgias (TACs) are a group 
of primary headaches that includes cluster headache, 
paroxysmal hemicrania, and SUNCT (short-lasting uni- 
lateral neuralgiform headache attacks with conjunctival 
injection and fearing) . TACs are characterized by rela- 
tively short-lasting attacks of head pain associated with 
cranial autonomic symptoms, such as lacrimation, con- 
junctival injection, or nasal congestion (Table 6-8). Pain 
is usually severe and may occur more than once a day. 



Because of the associated nasal congestion or rhinorrhea, 
patients are often misdiagnosed with "sinus headache" 
and treated with decongestants, which are ineffective. 

TACs must be differentiated from short-lasting head- 
aches that do not have prominent cranial autonomic syn- 
dromes, notably trigeminal neuralgia, primary stabbing 
headache, and hypnic headache. The cycling pattern and 
length, frequency, and timing of attacks are useful in 
classifying patients. Patients with TACs should undergo 
pituitary imaging and pituitary function tests as there is 
an excess of TAC presentations in patients with pituitary 
tumor-related headache 

Cluster Headache 

Cluster headache is a rare form of primary headache 
with a population frequency of 0.1%. The pain is deep, 
usually retroorbital, often excruciating in intensity, non- 
fluctuating, and explosive in quality. A core feature of 
cluster headache is periodicity. At least one of the daily 
attacks of pain recurs at about the same hour each day 
for the duration of a cluster bout. The typical cluster 
headache patient has daily bouts of one to two attacks of 
relatively short-duration unilateral pain for 8—10 weeks 
a year; this is usually followed by a pain-free interval that 
averages 1 year. Cluster headache is characterized as 
chronic when there is no period of sustained remission. 
Patients are generally perfectly well between episodes. 



61 



QJ 
QJ 



TABLE 6-8 



CLINICAL FEATURES OF THE TRIGEMINAL AUTONOMIC CEPHALALGIAS 





CLUSTER HEADACHE 


PAROXYSMAL HEMICRANIA 


SUNCT 


Gender 


M>F 


F=M 


F~M 


Pain 








Type 


Stabbing, boring 


Throbbing, boring, stabbing 


Burning, stabbing, sharp 


Severity 


Excruciating 


Excruciating 


Severe to excruciating 


Site 


Orbit, temple 


Orbit, temple 


Periorbital 


Attack frequency 


1 /alternate day-8/d 


1 -40/d (>5/d for more than 
half the time) 


3-200/d 


Duration of attack 


15-180 min 


2-30 min 


5-240 s 


Autonomic features 


Yes 


Yes 


Yes (prominent conjunctival 
injection and lacrimation) 3 


Migrainous features 6 


Yes 


Yes 


Yes 


Alcohol trigger 


Yes 


No 


No 


Cutaneous triggers 


No 


No 


Yes 


Indomethacin effect 


— 


Yes c 


— 


Abortive treatment 


Sumatriptan injection 
or nasal spray 
Oxygen 


No effective treatment 


Lidocaine (IV) 


Prophylactic 


Verapamil 


Indomethacin 


Lamotrigine 


treatment 


Methysergide 




Topiramate 




Lithium 




Gabapentin 



a lf conjunctival injection and tearing not present, consider SUNA. 

b Nausea, photophobia, or phonophobia; photophobia and phonophobia are typically unilateral on the side of the pain. 

indicates complete response to indomethacin. 

Note: SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. 



62 



a> 
ST 
o' 



o 
in 



a> 



Onset is nocturnal in about 50% of patients, and men 
are affected three times more often than women. 
Patients with cluster headache tend to move about dur- 
ing attacks, pacing, rocking, or rubbing their head for 
relief; some may even become aggressive during attacks. 
This is in sharp contrast to patients with migraine, who 
prefer to remain motionless during attacks. 

Cluster headache is associated with ipsilateral symp- 
toms of cranial parasympathetic autonomic activation: 
conjunctival injection or lacrimation, rhinorrhea or nasal 
congestion, or cranial sympathetic dysfunction such as 
ptosis. The sympathetic deficit is peripheral and likely to 
be due to parasympathetic activation with injury to ascend- 
ing sympathetic fibers surrounding a dilated carotid artery 
as it passes into the cranial cavity. When present, photo- 
phobia and phonophobia are far more likely to be unilat- 
eral and on the same side of the pain, rather than bilateral, 
as is seen in migraine. This phenomenon of unilateral 
photophobia/phonophobia is characteristic of TACs. 
Cluster headache is likely to be a disorder involving 
central pacemaker neurons in the region of the posterior 
hypothalamus (Fig. 6-2). 



TABLE 6-9 



PREVENTIVE MANAGEMENT OF CLUSTER HEADACHE 



"k 



Treatment: 
CLUSTER HEADACHE 



The most satisfactory treatment is the administration of 
drugs to prevent cluster attacks until the bout is over. 
However, treatment of acute attacks is required for all 
cluster headache patients at some time. 

ACUTE ATTACK TREATMENT Cluster headache 
attacks peak rapidly, and thus a treatment with quick 
onset is required. Many patients with acute cluster 
headache respond very well to oxygen inhalation. This 
should be given as 100% oxygen at 10-12 L/min for 
15-20 min. It appears that high flow and high oxygen 
content are important. Sumatriptan 6 mg subcuta- 
neously is rapid in onset and will usually shorten an 
attack to 10-15 min; there is no evidence of tachyphy- 
laxis. Sumatriptan (20 mg) and zolmitriptan (5 mg) nasal 
sprays are both effective in acute cluster headache, 
offering a useful option for patients who may not wish 
to self-inject daily. Oral sumatriptan is not effective for 
prevention or for acute treatment of cluster headache. 

PREVENTIVE TREATMENTS (Table 6-9) The 

choice of a preventive treatment in cluster headache 
depends in part on the length of the bout. Patients with 
long bouts or those with chronic cluster headache 
require medicines that are safe when taken for long 
periods. For patients with relatively short bouts, limited 
courses of oral glucocorticoids or methysergide (not 
available in the United States) can be very useful. A 10- 
day course of prednisone, beginning at 60 mg daily for 7 
days and followed by a rapid taper, may interrupt the 
pain bout for many patients. When ergotamine (1-2 mg) 



SHORT-TERM PREVENTION LONG-TERM PREVENTION 




Episodic Cluster Headache & 


Episodic Cluster 


Prolonged Chronic 


Headache 


Cluster Headache 


Prednisone 1 mg/kg up 


Verapamil 160-960 mg/d 


to 60 mg qd, tapering 


Lithium 400-800 mg/d 


over 21 days 


Methysergide 3-12 mg/d 


Methysergide 3-12 mg/d 


Topiramate 3 100-400 mg/d 


Verapamil 160-960 mg/d 


Gabapentin 3 1200-3600 mg/d 


Greater occipital nerve 


Melatonin 3 9-12 mg/d 


injection 





a Unproven but of potential benefit. 

is used, it is most effective when given 1-2 h before an 
expected attack. Patients who use ergotamine daily 
must be educated regarding the early symptoms of 
ergotism, which may include vomiting, numbness, tin- 
gling, pain, and cyanosis of the limbs; a weekly limit of 
14 mg should be adhered to. Lithium (600-900 mg qd) 
appears to be particularly useful for the chronic form of 
the disorder. 

Many experts favor verapamil as the first-line preven- 
tive treatment for patients with chronic cluster headache 
or prolonged bouts. While verapamil compares favorably 
with lithium in practice, some patients require verapamil 
doses far in excess of those administered for cardiac disor- 
ders. The initial dose range is 40-80 mg twice daily; effec- 
tive doses may be as high as 960 mg/d. Side effects such 
as constipation and leg swelling can be problematic. Of 
paramount concern, however, is the cardiovascular safety 
of verapamil, particularly at high doses. Verapamil can 
cause heart block by slowing conduction in the atrioven- 
tricular node, a condition that can be monitored by fol- 
lowing the PR interval on a standard ECG. Approximately 
20% of patients treated with verapamil develop ECG 
abnormalities, which can be observed with doses as low 
as 240 mg/d; these abnormalities can worsen over time in 
patients on stable doses. A baseline ECG is recommended 
for all patients. The ECG is repeated 10 days after a dose 
change in those patients whose dose is being increased 
above 240 mg daily. Dose increases are usually made in 
80-mg increments. For patients on long-term verapamil, 
ECG monitoring every 6 months is advised. 

NEUROSTIMULATION THERAPY When med- 
ical therapies fail in chronic cluster headache, neu- 
rostimulation therapy strategies can be employed. 
Deep-brain stimulation of the region of the posterior 
hypothalamic gray matter has proven successful in a 
substantial proportion of patients. Favorable results 
have also been reported with the less-invasive approach 
of occipital nerve stimulation. 



Paroxysmal Hemicrania 

Paroxysmal hemicrania (PH) is characterized by frequent 
unilateral, severe, short-lasting episodes of headache. Like 
cluster headache, the pain tends to be retroorbital but 
may be experienced all over the head and is associated 
with autonomic phenomena such as lacrimation and nasal 
congestion. Patients with remissions are said to have 
episodic PH, while those with the nonremitting form are 
said to have chronic PH. The essential features of PH are: 
unilateral, very severe pain; short-lasting attacks (2-45 min); 
very frequent attacks (usually more than five a day); marked 
autonomic features ipsilateral to the pain; rapid course 
(<72 h); and excellent response to indomethacin. In con- 
trast to cluster headache, which predominantly affects 
males; the male:female ratio in PH is close to 1:1. 

Indomethacin (25—75 mg tid), which can completely 
suppress attacks of PH, is the treatment of choice. Although 
therapy may be complicated by indomethacin-induced 
gastrointestinal side effects, currently there are no consis- 
tently effective alternatives. Topiramate is helpful in some 
cases. Piroxicam has been used, although it is not as effec- 
tive as indomethacin. Verapamil, an effective treatment for 
cluster headache, does not appear to be useful for PH. In 
occasional patients, PH can coexist with trigeminal neural- 
gia (PH-tic syndrome); similar to cluster-tic syndrome, each 
component may require separate treatment. 

Secondary PH has been reported with lesions in the 
region of the sella turcica, including arteriovenous malfor- 
mation, cavernous sinus meningioma, and epidermoid 
tumors. Secondary PH is more likely if the patient requires 
high doses (>200 mg/d) of indomethacin. In patients with 
apparent bilateral PH, raised CSF pressure should be sus- 
pected. It is important to note that indomethacin reduces 
CSF pressure. When a diagnosis of PH is considered, MRI 
is indicated to exclude a pituitary lesion. 

SUNCT/SUNA 

SUNCT is a rare primary headache syndrome charac- 
terized by severe, unilateral orbital or temporal pain that 
is stabbing or throbbing in quality. Diagnosis requires at 
least 20 attacks, lasting for 5-240 s; ipsilateral conjuncti- 
val injection and lacrimation should be present. In some 
patients conjunctival injection or lacrimation are miss- 
ing, and the diagnosis of SUNA (short-lasting unilateral 
neuralgiform headache attacks with cranial autonomic 
symptoms) has been suggested. 

^H Diagnosis 

The pain of SUNCT/SUNA is unilateral and may be 
located anywhere in the head. Three basic patterns can 
be seen: single stabs, which are usually short-lived; groups 
of stabs; or a longer attack comprising many stabs between 
which the pain does not completely resolve, thus giving 
a "saw-tooth" phenomenon with attacks lasting many 



minutes. Each pattern may be seen in the context of an 
underlying continuous head pain. Characteristics that 
lead to a suspected diagnosis of SUNCT are the cuta- 
neous (or other) triggerability of attacks, a lack of refrac- 
tory period to triggering between attacks, and the lack of 
a response to indomethacin. Apart from trigeminal sen- 
sory disturbance, the neurologic examination is normal 
in primary SUNCT. 

The diagnosis of SUNCT is often confused with 
trigeminal neuralgia (TN) particularly in first-division 
TN (Chap. 29). Minimal or no cranial autonomic symp- 
toms and a clear refractory period to triggering indicate 
a diagnosis of TN. 

^H Secondary (Symptomatic) SUNCT 

SUNCT can be seen with posterior fossa or pituitary 
lesions. All patients with SUNCT/SUNA should be 
evaluated with pituitary function tests and a brain MRI 
with pituitary views. 



63 



Be 



Treatment: 
SUNCT/SUNA 



ABORTIVE THERAPY Therapy of acute attacks is 
not a useful concept in SUNCT/SUNA since the attacks 
are of such short duration. However, intravenous lido- 
caine, which arrests the symptoms, can be used in hospi- 
talized patients. 

PREVENTIVE THERAPY Long-term prevention 
to minimize disability and hospitalization is the goal of 
treatment. The most effective treatment for prevention is 
lamotrigine, 200-400 mg/d. Topiramate and gabapentin 
may also be effective. Carbamazepine, 400-500 mg/d, 
has been reported by patients to offer modest benefit. 

Surgical approaches such as microvascular decom- 
pression or destructive trigeminal procedures are sel- 
dom useful and often produce long-term complica- 
tions. Greater occipital nerve injection has produced 
limited benefit in some patients. Mixed success with 
occipital nerve stimulation has been observed. Com- 
plete control with deep-brain stimulation of the poste- 
rior hypothalamic region was reported in a single 
patient. For intractable cases, short-term prevention 
with intravenous lidocaine can be effective. 



CHRONIC DAILY HEADACHE 

The broad diagnosis of chronic daily headache (CDH) 
can be applied when a patient experiences headache on 
15 days or more per month. CDH is not a single entity; 
it encompasses a number of different headache syn- 
dromes, including chronic TTH as well as headache sec- 
ondary to trauma, inflammation, infection, medication 



QJ 



64 TABLE 6-10 



CLASSIFICATION OF CHRONIC DAILY HEADACHE 



PRIMARY 



a> 
ST 
o' 



o 

CO 



a> 



>4 H DAILY 


<4 H DAILY 


SECONDARY 


Chronic migraine 3 


Chronic cluster 


Posttraumatic 




headache" 


Head injury 

Iatrogenic 

Postinfectious 


Chronic tension- 


Chronic 




type headache 3 


paroxysmal 


Inflammatory, such as 




hemicrania 


Giant cell arteritis 
Sarcoidosis 
Behget's syndrome 


Hemicrania 


SUNCT/SUNA 


Chronic CNS 


continua 3 




infection 


New daily 


Hypnic 


Medication-overuse 


persistent 


headache 


headache 3 


headache 3 







a May be complicated by analgesic overuse. 

b Some patients may have headache > 4 h per day. 

Note: SUNCT, short-lasting unilateral neuralgiform neadache attacks 

with conjunctival injection and fearing; SUNA, short-lasting unilateral 

neuralgiform headache attacks with cranial autonomic symptoms. 



overuse, and other causes (Table 6-10). Population-based 
estimates suggest that about 4% of adults have daily or 
near-daily headache. Daily headache may be primary or 
secondary an important consideration in guiding man- 
agement of this complaint. 



Approach to the Patient: 

CHRONIC DAILY HEADACHE 

The first step in the management of patients with 
CDH is to diagnose any underlying condition (Table 
6-10). For patients with primary headaches, diagnosis 
of the headache type will guide therapy. Preventive 
treatments such as tricyclics, either amitriptyline or 
doxepin at doses up to 1 mg/kg, are very useful in 
patients with CDH. Tricyclics are started in low doses 
(10—25 mg) daily and may be given 12 h before the 
expected time of awakening in order to avoid excess 
morning sleepiness. Anticonvulsants, such as topira- 
mate, valproate, and gabapentin, are also useful in 
migraineurs. Flunarizine can also be very effective for 
some patients, as can methysergide or phenelzine. 

MANAGEMENT OF MEDICALLY INTRACTABLE 
DISABLING CHRONIC DAILY HEADACHE The 

management of medically intractable headache is diffi- 
cult. At this time, the only promising approach is occip- 
ital nerve stimulation, which appears to modulate thala- 
mic processing in migraine and has shown promise in 
both chronic cluster headache and hemicrania continua 



(see below). Clinical trials using botulinum toxin in 
chronic migraine have failed to show any objective 
benefit. 

MEDICATION-OVERUSE HEADACHE Overuse 
of analgesic medication for headache can aggravate 
head-ache frequency and induce a state of refractory 
daily or near-daily headache called medication-overuse 
headache. A proportion of patients who stop taking 
analgesics will experience substantial improvement in 
the severity and frequency of their headache. However, 
even after cessation of analgesic use, many patients 
continue to have headache, although they may feel 
clinically improved in some way, especially if they have 
been using codeine or barbiturates regularly. The resid- 
ual symptoms probably represent the underlying 
headache disorder. 

Management of Medication Overuse: Out- 
patients For patients who overuse medications, it 
is essential that analgesic use be reduced and elimi- 
nated. One approach is to reduce the medication dose 
by 10% every 1—2 weeks. Immediate cessation of anal- 
gesic use is possible for some patients, provided there is 
no contraindication. Both approaches are facilitated by 
the use of a medication diary maintained during the 
month or two before cessation; this helps to identify 
the scope of the problem. A small dose of an NSAID 
such as naproxen, 500 mg bid if tolerated, will help 
relieve residual pain as analgesic use is reduced. NSAID 
overuse is not usually a problem for patients with daily 
headache when the dose is taken once or twice daily; 
however, overuse problems may develop with more 
frequent dosing schedules. Once the patient has sub- 
stantially reduced analgesic use, a preventive medica- 
tion should be introduced. It must be emphasized that 
preventives generally do not work in the presence of analgesic 
overuse. The most common cause of unresponsiveness 
to treatment is the use of a preventive when analgesics 
continue to be used regularly. For some patients, dis- 
continuing analgesics is very difficult; often the best 
approach is to directly inform the patient that some 
degree of pain is inevitable during this initial period. 

Management of Medication Overuse: Inpa- 
tients Some patients will require hospitalization for 
detoxification. Such patients have typically failed efforts 
at outpatient withdrawal or have a significant medical 
condition, such as diabetes mellitus, which would com- 
plicate withdrawal as an outpatient. Following admis- 
sion to the hospital, acute medications are withdrawn 
completely on the first day, in the absence of a con- 
traindication. Antiemetics and fluids are administered as 
required; clonidine is used for opiate withdrawal symp- 
toms. For acute intolerable pain during the waking hours 
aspirin, 1 g (not approved in United States) intravenously, 



TABLE 6-11 



DIFFERENTIAL DIAGNOSIS OF NEW DAILY 
PERSISTENT HEADACHE 



PRIMARY 


SECONDARY 


Migrainous-type 


Subarachnoid hemorrhage 


Featureless (tension-type) 


Low CSF volume headache 




Raised CSF pressure 




headache 




Posttraumatic headache 3 




Chronic meningitis 



includes postinfectious forms. 



is useful. Intramuscular chlorpromazine can be helpful 
at night; patients must be adequately hydrated. If the 
patient does not improve within 3—5 days, a course of 
intravenous dihydroergotamine (DHE) can be 
employed. DHE, administered every 8 h for 3 consecu- 
tive days, can induce a significant remission that allows 
a preventive treatment to be established. 5-HT 3 antago- 
nists, such as ondansetron or granisetron, are often 
required with DHE to prevent significant nausea. 

NEW DAILY PERSISTENT HEADACHE New 

daily persistent headache (NDPH) is a clinically dis- 
tinct syndrome; its causes are listed in Table 6-11. 

Clinical Presentation The patient with NDPH 
presents with headache on most if not all days; the 
onset is recent and clearly recalled by the patient. The 
headache usually begins abruptly, but onset may be 
more gradual; evolution over 3 days has been pro- 
posed as the upper limit for this syndrome. Patients 
typically recall the exact day and circumstances of the 
onset of headache; the new, persistent head pain does 
not remit. The first priority is to distinguish between 
a primary and a secondary cause of this syndrome. 
Subarachnoid hemorrhage is the most serious of the 
secondary causes and must be excluded either by his- 
tory or appropriate investigation (Chap. 22) . 

SECONDARY NDPH 

Low CSF volume headache In these syndromes, 
head pain is positional: it begins when the patient sits or 
stands upright and resolves upon reclining. The pain, 
which is occipitofrontal, is usually a dull ache but may 
be throbbing. Patients with chronic low CSF volume 
headache typically present with a history of headache 
from one day to the next that is generally not present 
on waking but worsens during the day. Recumbency 
usually improves the headache within minutes, but it 
takes only minutes to an hour for the pain to return 
when the patient resumes an upright position. 

The most common cause of headache due to persis- 
tent low CSF volume is CSF leak following lumbar 



puncture (LP). Post-LP headache usually begins within 
48 h but may be delayed for up to 12 days. Its inci- 
dence is between 10 and 30%. Beverages with caffeine 
may provide temporary relief. Besides LP, index events 
may include epidural injection or a vigorous Valsalva 
maneuver, such as from lifting, straining, coughing, 
clearing the eustachian tubes in an airplane, or multiple 
orgasms. Spontaneous CSF leaks are well recognized, 
and the diagnosis should be considered whenever the 
headache history is typical, even when there is no 
obvious index event. As time passes from the index 
event, the postural nature may become less apparent; 
cases in which the index event occurred several years 
before the eventual diagnosis have been recognized. 
Symptoms appear to result from low volume rather 
than low pressure: although low CSF pressures, typi- 
cally 0-50 mmH 2 0, are usually identified, a pressure as 
high as 140 mmH 2 has been noted with a docu- 
mented leak. Postural orthostatic tachycardia syndrome 
[POTS (Chap. 28)] can present with orthostatic headache 
similar to low CSF volume headache and is a diagnosis 
that needs consideration here. 

When imaging is indicated to identify the source of a 
presumed leak, an MRI with gadolinium is the initial 
study of choice (Fig. 6-5). A striking pattern of diffuse 
meningeal enhancement is so typical that in the appro- 
priate clinical context the diagnosis is established. Chiari 
malformations may sometimes be noted on MRI; in 



65 




FIGURE 6-5 

Magnetic resonance image showing diffuse meningeal 
enhancement after gadolinium administration in a patient 
with low CSF volume headache. High-resolution T1 weighted 
MRI obtained using voxel-based morphometry demonstrates 
increased gray matter activity, lateralized to the side of pain 
in a patient with cluster headache. (From A May et al: Nat 
Med 5:836, 1999.) 



QJ 
QJ 



66 



a> 

5T 

o' 



o 
in 



a> 



such cases surgery to decompress the posterior fossa 
usually worsens the headache. The source of CSF leak- 
age may be identified by spinal MRI, by CT myelo- 
gram, or with m In-DTPA CSF studies; in the absence 
of a direcdy identified site of leakage, early emptying of 
ln In-DTPA tracer into the bladder or slow progress of 
tracer across the brain suggests a CSF leak. 

Initial treatment for low CSF volume headache is 
bed rest. For patients with persistent pain, intravenous 
caffeine (500 mg in 500 mL saline administered over 
2 h) is often very effective. An EKG to screen for 
arrhythmia should be performed before administra- 
tion. It is reasonable to administer at least two infusions 
of caffeine before embarking on additional tests to 
identify the source of the CSF leak. Since intravenous 
caffeine is safe and can be curative, it spares many 
patients the need for further investigations. If unsuc- 
cessful, an abdominal binder may be helpful. If a leak 
can be identified, an autologous blood patch is usually 
curative. A blood patch is also effective for post-LP 
headache; in this setting the location is empirically 
determined to be the site of the LP. In patients with 
intractable pain, oral theophylline is a useful alternative; 
however, its effect is less rapid than caffeine. 

Raised CSF pressure headache Raised CSF 
pressure is well recognized as a cause of headache. Brain 
imaging can often reveal the cause, such as a space- 
occupying lesion. NDPH due to raised CSF pressure 
can be the presenting symptom for patients with idio- 
pathic intracranial hypertension (pseudotumor cerebri) 
without visual problems, particularly when the fundi 
are normal. Persistendy raised intracranial pressure can 
trigger chronic migraine. These patients typically pre- 
sent with a history of generalized headache that is pre- 
sent on waking and improves as the day goes on. It is 
generally worse with recumbency. Visual obscurations 
are frequent. The diagnosis is relatively straightforward 
when papilledema is present, but the possibility must be 
considered even in patients without fundoscopic 
changes. Formal visual-field testing should be per- 
formed even in the absence of overt ophthalmic 
involvement. Headache on rising in the morning or 
nocturnal headache is also characteristic of obstructive 
sleep apnea or poorly controlled hypertension. 

Evaluation of patients suspected to have raised CSF 
pressure requires brain imaging. It is most efficient to 
obtain an MRI, including an MR venogram as the 
initial study. If there are no contraindications, the 
CSF pressure should be measured by LP; this should 
be done when the patient is symptomatic so that 
both the pressure and the response to removal of 
20—30 mL of CSF can be determined. An elevated 
opening pressure and improvement in headache fol- 
lowing removal of CSF is diagnostic. 



Initial treatment is with acetazolamide (250—500 mg 
bid); the headache may improve within weeks. If 
ineffective, topiramate is the next treatment of choice; 
it has many actions that may be useful in this setting, 
including carbonic anhydrase inhibition, weight loss, 
and neuronal membrane stabilization, likely mediated 
via effects on phosphorylation pathways. Severely dis- 
abled patients who do not respond to medical treat- 
ment require intracranial pressure monitoring and may 
require shunting. 

Post-traumatic headache A traumatic event 
can trigger a headache process that lasts for many 
months or years after the event. The term trauma is 
used in a very broad sense: headache can develop fol- 
lowing an injury to the head, but it can also develop 
after an infectious episode, typically viral meningitis, a 
flulike illness, or a parasitic infection. Complaints of 
dizziness, vertigo, and impaired memory can accom- 
pany the headache. Symptoms may remit after several 
weeks or persist for months and even years after the 
injury. Typically the neurologic examination is normal 
and CT or MRI studies are unrevealing. Chronic sub- 
dural hematoma may on occasion mimic this disorder. 
In one series, one-third of patients with NDPH 
reported headache beginning after a transient flulike 
illness characterized by fever, neck stiffness, photopho- 
bia, and marked malaise. Evaluation reveals no appar- 
ent cause for the headache. There is no convincing 
evidence that persistent Epstein-Barr infection plays a 
role in this syndrome. A complicating factor is that 
many patients undergo LP during the acute illness; 
iatrogenic low CSF volume headache must be consid- 
ered in these cases. Post-traumatic headache may also 
be seen after carotid dissection and subarachnoid 
hemorrhage, and following intracranial surgery. The 
underlying theme appears to be that a traumatic event 
involving the pain-producing meninges can trigger a 
headache process that lasts for many years. 

Treatment is largely empirical. Tricyclic antidepres- 
sants, notably amitriptyline, and anticonvulsants such 
as topiramate, valproate, and gabapentin, have been used 
with reported benefit. The MAOI phenelzine may 
also be useful in carefully selected patients. The headache 
usually resolves within 3-5 years, but it can be quite 
disabling. 

Primary NDPH Primary NDPH occurs in both 
males and females. It can be of the migrainous type, 
with features of migraine, or it can be featureless, 
appearing as new-onset TTH (Table 6-11). Migrain- 
ous features are common and include unilateral 
headache and throbbing pain; each feature is present 
in about one-third of patients. Nausea, photophobia, 
and/or phonophobia occur in about half of patients. 



Some patients have a previous history of migraine; 
however, the proportion of NDPH sufferers with 
preexisting migraine is no greater than the frequency 
of migraine in the general population. At 24 months, 
~86% of patients are headache-free. Treatment of 
migrainous-type primary NDPH consists of using 
the preventive therapies effective in migraine (Table 
6-7). Featureless NDPH is one of the primary 
headache forms most refractory to treatment. Stan- 
dard preventive therapies can be offered but are often 
ineffective. 



OTHER PRIMARY HEADACHES 
Hemicrania Continua 

The essential features of hemicrania continua are moder- 
ate and continuous unilateral pain associated with fluctu- 
ations of severe pain; complete resolution of pain with 
indomethacin; and exacerbations that may be associated 
with autonomic features, including conjunctival injec- 
tion, lacrimation, and photophobia on the affected side. 
The age of onset ranges from 11 to 58 years; women are 
affected twice as often as men. The cause is unknown. 



Be 



Treatment: 

PRIMARY STABBING HEADACHE 



67 



Be 



Treatment: 
HEMICRANIA CONTINUA 



Treatment consists of indomethacin; other NSAIDs 
appear to be of little or no benefit. The intramuscular 
injection of 100 mg indomethacin has been proposed 
as a diagnostic tool; administration with a placebo 
injection has been recommended. Alternatively, a trial of 
oral indomethacin, starting with 25 mg tid, then 50 mg 
tid, and then 75 mg tid, can be given. Up to 2 weeks may 
be necessary to assess whether a dose has a useful 
effect. Topiramate can be helpful in some patients. 
Occipital nerve stimulation may have a role in patients 
with hemicrania continua who are unable to tolerate 
indomethacin. 



Primary Stabbing Headache 

The essential features of primary stabbing headache are 
stabbing pain confined to the head or, rarely, the face, last- 
ing from 1 to many seconds or minutes and occurring as 
a single stab or a series of stabs; absence of associated cra- 
nial autonomic features; absence of cutaneous triggering 
of attacks; and a pattern of recurrence at irregular intervals 
(hours to days). The pains have been variously described 
as "ice-pick pains" or "jabs and jolts ."They are more com- 
mon in patients with other primary headaches, such as 
migraine, theTACs, and hemicrania continua. 



The response of primary stabbing headache to indo- 
methacin (25-50 mg two to three times daily) is usually 
excellent. As a general rule the symptoms wax and 
wane, and after a period of control on indomethacin, it is 
appropriate to withdraw treatment and observe the 
outcome. 



Primary Cough Headache 

Primary cough headache is a generalized headache that 
begins suddenly, lasts for several minutes, and is precipi- 
tated by coughing; it is preventable by avoiding coughing 
or other precipitating events, which can include sneezing, 
straining, laughing, or stooping. In all patients with this 
syndrome serious etiologies must be excluded before a 
diagnosis of "benign" primary cough headache can be 
established. A Chiari malformation or any lesion causing 
obstruction of CSF pathways or displacing cerebral struc- 
tures can be the cause of the head pain. Other conditions 
that can present with cough or exertional headache as the 
initial symptom include cerebral aneurysm, carotid steno- 
sis, and vertebrobasilar disease. Benign cough headache 
can resemble benign exertional headache (below), but 
patients with the former condition are typically older. 



Be 



Treatment: 

PRIMARY COUGH HEADACHE 



Indomethacin 25-50 mg two to three times daily is the 
treatment of choice. Some patients with cough headache 
obtain pain relief with LP; this is a simple option when 
compared to prolonged use of indomethacin, and it is 
effective in about one-third of patients. The mechanism 
of this response is unclear. 



Primary Exertional Headache 

Primary exertional headache has features resembling 
both cough headache and migraine. It may be precipi- 
tated by any form of exercise; it often has the pulsatile 
quality of migraine. The pain, which can last from 5 min 
to 24 h, is bilateral and throbbing at onset; migrainous 
features may develop in patients susceptible to migraine. 
Primary exertional headache can be prevented by avoid- 
ing excessive exertion, particularly in hot weather or at 
high altitude. 

The mechanism of primary exertional headache is 
unclear. Acute venous distension likely explains one syn- 
drome, the acute onset of headache with straining and 
breath holding, as in weightlifter's headache. As exertion 



QJ 
QJ 



68 can result in headache in a number of serious underlying 
conditions, these must be considered in patients with exer- 
tional headache. Pain from angina may be referred to the 
head, probably by central connections of vagal afferents, and 
may present as exertional headache (cardiac cephalgia) . The 
link to exercise is the main clinical clue that headache is of 
cardiac origin. Pheochromocytoma may occasionally cause 
exertional headache. Intracranial lesions and stenosis of the 
carotid arteries are other possible etiologies. 



advice about ceasing sexual activity if a mild, warning 
headache develops. Propranolol can be used to prevent 
headache that recurs regularly or frequently, but the 
dosage required varies from 40 to 200 mg/d. An alterna- 
tive is the calcium channel-blocking agent diltiazem, 60 
mg tid. Ergotamine (1 mg) or indomethacin (25-50 mg) 
taken about 30-45 min prior to sexual activity can also 
be helpful. 



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P Treatment: 

fr PRIMARY EXERTIONAL HEADACHE 

Exercise regimens should begin modestly and progress 
gradually to higher levels of intensity. Indomethacin at 
daily doses from 25 to 150 mg is generally effective in 
benign exertional headache. Indomethacin (50 mg), 
ergotamine (1 mg orally), dihydroergotamine (2 mg by 
nasal spray), or methysergide (1-2 mg orally given 30-45 
min before exercise) are useful prophylactic measures. 



Primary Sex Headache 

Sex headache is precipitated by sexual excitement. The 
pain usually begins as a dull bilateral headache which sud- 
denly becomes intense at orgasm. The headache can be 
prevented or eased by ceasing sexual activity before orgasm. 
Three types of sex headache are reported: a dull ache in 
the head and neck that intensifies as sexual excitement 
increases; a sudden, severe, explosive headache occurring at 
orgasm; and a postural headache developing after coitus 
that resembles the headache of low CSF pressure. The lat- 
ter arises from vigorous sexual activity and is a form of low 
CSF pressure headache. Headaches developing at the time 
of orgasm are not always benign; 5—12% of cases of sub- 
arachnoid hemorrhage are precipitated by sexual inter- 
course. Sex headache is reported by men more often than 
women and may occur at any time during the years of 
sexual activity. It may develop on several occasions in suc- 
cession and then not trouble the patient again, even with- 
out an obvious change in sexual activity. In patients who 
stop sexual activity when headache is first noticed, the pain 
may subside within a period of 5 min to 2 h. In about half 
of patients, sex headache will subside within 6 months. 
About half of patients with sex headache have a history of 
exertional headaches, but there is no excess of cough 
headache. Migraine is probably more common in patients 
with sex headache. 



"x 



Treatment: 

PRIMARY SEX HEADACHE 



Benign sex headaches recur irregularly and infrequently. 
Management can often be limited to reassurance and 



Primary Thunderclap Headache 

Sudden onset of severe headache may occur in the absence 
of any known provocation. The differential diagnosis 
includes the sentinel bleed of an intracranial aneurysm, cer- 
vicocephalic arterial dissection, and cerebral venous throm- 
bosis. Headaches of explosive onset may also be caused by 
the ingestion of sympathomimetic drugs or of tyramine- 
containing foods in a patient who is taking MAOIs, or they 
may be a symptom of pheochromocytoma. Whether thun- 
derclap headache can be the presentation of an unruptured 
cerebral aneurysm is uncertain. When neuroimaging studies 
and LP exclude subarachnoid hemorrhage, patients with 
thunderclap headache usually do very well over the long 
term. In one study of patients whose CT scans and CSF 
findings were negative, ~15% had recurrent episodes of 
thunderclap headache, and nearly half subsequently devel- 
oped migraine or tension-type headache. 

The first presentation of any sudden-onset severe 
headache should be vigorously investigated with neu- 
roimaging (CT or, when possible, MRI with MR 
angiography) and CSF examination. Formal cerebral 
angiography should be reserved for those cases in which 
no primary diagnosis is forthcoming and for clinical 
situations that are particularly suggestive of intracranial 
aneurysm. Reversible segmental cerebral vasoconstric- 
tion may be seen in primary thunderclap headache 
without an intracranial aneurysm. In the presence of 
posterior leukoencephalopathy, the differential diagnosis 
includes cerebral angiitis, drug toxicity (cyclosporine, 
intrathecal methotrexate/cytarabine, pseudoephedrine, 
or cocaine), posttransfusion effects, and postpartum 
angiopathy. Treatment with nimodipine may be helpful, 
although by definition the vasoconstriction of primary 
thunderclap headache resolves spontaneously. 

Hypnic Headache 

This headache syndrome typically begins a few hours after 
sleep onset. The headaches last from 15 to 30 min and are 
typically moderately severe and generalized, although 
they may be unilateral and can be throbbing. Patients may 
report falling back to sleep only to be awakened by a fur- 
ther attack a few hours later; up to three repetitions of 
this pattern occur through the night. Daytime naps can 
also precipitate head pain. Most patients are women, and 



the onset is usually after age 60. Headaches are bilateral in 
most, but may be unilateral. Photophobia or phonopho- 
bia and nausea are usually absent. The major secondary 
consideration in this headache type is poorly controlled 
hypertension; 24-h blood pressure monitoring is recom- 
mended to detect this treatable condition. 



Be 



Treatment: 
HYPNIC HEADACHE 



Patients with hypnic headache generally respond to a 
bedtime dose of lithium carbonate (200-600 mg). For 
those intolerant of lithium, verapamil (160 mg) or 
methysergide (1-4 mg at bedtime) may be alternative 
strategies. One to two cups of coffee or caffeine, 60 mg 
orally, at bedtime may be effective in approximately 
one-third of patients. Case reports suggest that flunar- 
izine,5 mg nightly, can be effective. 



FURTHER READINGS 

ClTTADINI E et al: Paroxysmal hemicrania: A prospective clinical 

study of 31 cases. Brain 131:1142,2008 
COHEN AS et al: Trigeminal autonomic cephalalgias: Current and future 

treatments. Headache 47:969, 2007 
GOADSBY PJ: Is medication-overuse headache a distinct biological 

entity? Nat Clin Pract Neurol 2:401, 2006 
HAUGE AW et al: Effects of tonabersat on migraine with aura: a ran- 
domised, double-blind, placebo-controlled crossover study. Lancet 

Neurol 8:718, 2009 
HEADACHE Classification Committee of the International Headache 

Society: The international classification of headache disorders 

(second edition). Cephalalgia 24:1, 2004 
LANCE JW, Goadsby PJ: Mechanism and Management of Headache. New 

York, Elsevier, 2005 
LEVY M et al:The clinical characteristics of headache in patients with 

pituitary tumours. Brain 128:1921, 2005 
OLESEN J et al: The Headaches. Philadelphia, Lippincott, Williams & 

Wilkins, 2005 
SCHER Al et al: Migraine Headache in Middle Age and Late-Life 

Brain Infarcts. JAMA 301:2563, 2009. 



69 



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QJ 
Q. 
QJ 




John W. Engstrom 



Anatomy of the Spine 70 

Causes of Back Pain 74 

Congenital Anomalies of the Lumbar Spine 74 

Trauma 75 

Lumbar Disk Disease 75 

Degenerative Conditions 76 

Arthritis 77 

Neoplasms 77 

Infections/Inflammation 78 

Metabolic Causes 78 

Referred Pain from Visceral Disease 78 



Other Causes of Back Pain 79 

Pain In the Neck and Shoulder 82 

Trauma to the Cervical Spine 82 

Cervical Disk Disease 83 

Cervical Spondylosis 83 

Other Causes of Neck Pain 84 

Thoracic Outlet 84 

Brachial Plexus and Nerves 85 

Shoulder 85 

Further Readings 85 



The importance of back and neck pain in our society is 
underscored by the following: (1) the cost of back pain 
in the United States is ~$100 billion annually including 
direct health care expenses plus costs due to loss of pro- 
ductivity; (2) back symptoms are the most common 
cause of disability in those <45 years; (3) low back pain 
is the second most common reason for visiting a physi- 
cian in the United States; and (4) ~1% of the U.S. popu- 
lation is chronically disabled because of back pain. 



ANATOMY OF THE SPINE 

The anterior portion of the spine consists of cylindrical 
vertebral bodies separated by intervertebral disks and 
held together by the anterior and posterior longitudinal 
ligaments. The intervertebral disks are composed of a 
central gelatinous nucleus pulposus surrounded by a 
tough cartilaginous ring, the annulus fibrosis; disks are 
responsible for 25% of spinal column length (Figs. 7-1 
and 7-2). The disks are largest in the cervical and lumbar 
regions where movements of the spine are greatest. The 
disks are elastic in youth and allow the bony vertebrae 
to move easily upon each other. Elasticity is lost with 
age. The function of the anterior spine is to absorb the 
shock of body movements such as walking and running. 



70 



The posterior portion of the spine consists of the ver- 
tebral arches and seven processes. Each arch consists of 
paired cylindrical pedicles anteriorly and paired laminae 
posteriorly. The vertebral arch gives rise to two transverse 
processes laterally one spinous process posteriorly plus 
two superior and two inferior articular facets. The appo- 
sition of a superior and inferior facet constitutes a facet 
joint. The functions of the posterior spine are to protect 
the spinal cord and nerves within the spinal canal and to 
stabilize the spine by providing sites for the attachment 
of muscles and ligaments. The contraction of muscles 
attached to the spinous and transverse processes produces 
a system of pulleys and levers that results in flexion, 
extension, and lateral bending movements of the spine. 

Nerve root injury (radiculopathy) is a common cause 
of neck, arm, low back, and leg pain (Figs. 12-2 and 12-3). 
The nerve roots exit at a level above their respective 
vertebral bodies in the cervical region (the C7 nerve root 
exits at the C6-C7 level) and below their respective ver- 
tebral bodies in the thoracic and lumbar regions (the Tl 
nerve root exits at the T1-T2 level). The cervical nerve 
roots follow a short intraspinal course before exiting. By 
contrast, because the spinal cord ends at the vertebral LI 
or L2 level, the lumbar nerve roots follow a long 
intraspinal course and can be injured anywhere from the 
upper lumbar spine to their exit at the intervertebral 



Posterior 



Posterior 



Anterior 



71 



Spinous process 

Superior 
articular 
process 



Transverse 
process 

Spinal canal 



Lamina 




Superior articular 
process 

Transverse 
process 



Spinous 
process 



Superior vertebral 

notch 

Intervertebral 
foramen 



Intervertebral 
disk 



Pedicle 



Inferior articular 
process (facet) 




Body 



Inferior vertebral 
notch 



Anterior 



FIGURE 7-1 

Vertebral anatomy. (From A 
Gauthier Cornuelle, DH Gronefeld: 
Radiographic Anatomy Positioning. 
New York, McGraw-Hill, 1998; with 
permission.) 



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foramen. For example, disk herniation at the L4-L5 level 
commonly produces compression of the traversing SI 
nerve root (Fig. 7-3). 

Pain-sensitive structures in the spine include the 
periosteum of the vertebrae, dura, facet joints, annulus 



Cervical (7) 



Thoracic (12)^ 





Cervical 
curvature 



Lumbar 
curvature 



Sacral 
curvature \ 



Anterior view Right lateral view 

FIGURE 7-2 

Spinal column. (From A Gauthier Cornuelle, DH Gronefeld: 
Radiographic Anatomy Positioning. New York, McGraw-Hill, 
1998; with permission.) 



fibrosus of the intervertebral disk, epidural veins, and the 
posterior longitudinal ligament. Disease of these diverse 
structures may explain many cases of back pain without 
nerve root compression. The nucleus pulposus of the 
intervertebral disk is not pain-sensitive under normal 
circumstances. Pain sensation is conveyed partially by the 
sinuvertebral nerve that arises from the spinal nerve at 
each spine segment and reenters the spinal canal 
through the intervertebral foramen at the same level. 
The lumbar and cervical spine possesses the greatest 
potential for movement and injury. 







L5 Root 



Protruded 
L5-S1 disk " 



S1 Root 



S2 Root 



-~\ 



FIGURE 7-3 

Compression of L5 and S1 roots by herniated disks. 

(From RD Adams et al: Principles of Neurology, 8th ed. New 
York, McGraw-Hill, 2005; with permission.) 



72 



Approach to the Patient: 
BACK PAIN 



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TYPES OF BACK PAIN Understanding the type of 
pain experienced by the patient is the essential first step. 
Attention is also focused on identification of risk factors 
for serious underlying diseases; the majority of these are 
due to radiculopathy, fracture, tumor, infection, or 
referred pain from visceral structures (Table 7-1). 

Local pain is caused by stretching of pain-sensitive 
structures that compress or irritate sensory nerve 
endings. The site of the pain is near the affected part 
of the back. 

Pain referred to the back may arise from abdominal or 
pelvic viscera. The pain is usually described as pri- 
marily abdominal or pelvic but is accompanied by 
back pain and usually unaffected by posture. The 
patient may occasionally complain of back pain only. 

Pain of spine origin may be located in the back or 
referred to the buttocks or legs. Diseases affecting the 
upper lumbar spine tend to refer pain to the lumbar 
region, groin, or anterior thighs. Diseases affecting the 
lower lumbar spine tend to produce pain referred to 
the buttocks, posterior thighs, or rarely the calves or 
feet. Provocative injections into pain-sensitive struc- 
tures of the lumbar spine may produce leg pain that 
does not follow a dermatomal distribution. This "scle- 
rotomal" pain may explain some cases of back and leg 
pain without evidence of nerve root compression. 

Radicular back pain is typically sharp and radiates 
from the lumbar spine to the leg within the territory 
of a nerve root (see Lumbar Disk Disease, later in the 
chpater) . Coughing, sneezing, or voluntary contraction 



TABLE 7-1 



ACUTE LOW BACK PAIN: RISK FACTORS FOR AN 
IMPORTANT STRUCTURAL CAUSE 



History 

Pain worse at rest or at night 
Prior history of cancer 

History of chronic infection (esp. lung, urinary tract, skin) 
History of trauma 
Incontinence 
Age >50 years 
Intravenous drug use 
Glucocorticoid use 

History of a rapidly progressive neurologic deficit 
Examination 
Unexplained fever 
Unexplained weight loss 
Percussion tenderness over the spine 
Abdominal, rectal, or pelvic mass 
Patrick's sign or heel percussion sign 
Straight leg or reverse straight-leg raising signs 
Progressive focal neurologic deficit 



of abdominal muscles (lifting heavy objects or strain- 
ing at stool) may elicit the radiating pain. The pain 
may increase in postures that stretch the nerves and 
nerve roots. Sitting stretches the sciatic nerve (L5 and 
SI roots) because the nerve passes posterior to the 
hip. The femoral nerve (L2, L3, and L4 roots) passes 
anterior to the hip and is not stretched by sitting. The 
description of the pain alone often fails to distinguish 
between sclerotomal pain and radiculopathy. 

Pain associated with muscle spasm, although of obscure 
origin, is commonly associated with many spine disor- 
ders. The spasms are accompanied by abnormal pos- 
ture, taut paraspinal muscles, and dull pain. 

Knowledge of the circumstances associated with 
the onset of back pain is important -when weighing 
possible serious underlying causes for the pain. Some 
patients involved in accidents or work-related injuries 
may exaggerate their pain for the purpose of com- 
pensation or for psychological reasons. 

EXAMINATION OF THE BACK A physical 
examination that includes the abdomen and rectum is 
advisable. Back pain referred from visceral organs may 
be reproduced during palpation of the abdomen [pan- 
creatitis, abdominal aortic aneurysm (AAA)] or per- 
cussion over the costovertebral angles (pyelonephritis). 

The normal spine has cervical and lumbar lordosis, 
and a thoracic kyphosis. Exaggeration of these nor- 
mal alignments may result in hyperkyphosis of the 
thoracic spine or hyperlordosis of the lumbar spine. 
Inspection may reveal a lateral curvature of the spine 
(scoliosis) or an asymmetry in the paraspinal muscles, 
suggesting muscle spasm. Back pain of bony spine 
origin is often reproduced by palpation or percussion 
over the spinous process of the affected vertebrae. 

Forward bending is often limited by paraspinal 
muscle spasm; the latter may flatten the usual lumbar 
lordosis. Flexion of the hips is normal in patients with 
lumbar spine disease, but flexion of the lumbar spine 
is limited and sometimes painful. Lateral bending to 
the side opposite the injured spinal element may 
stretch the damaged tissues, worsen pain, and limit 
motion. Hyperextension of the spine (with the 
patient prone or standing) is limited when nerve root 
compression, facet joint pathology, or other bony 
spine disease is present. 

Pain from hip disease may mimic pain of lumbar 
spine disease. Hip pain can be reproduced by internal 
and external rotation at the hip with the knee and 
hip in flexion (Patrick sign) and by tapping the heel 
with the examiner's palm while the leg is extended. 

With the patient lying flat, passive flexion of the 
extended leg at the hip stretches the L5 and SI nerve 
roots and the sciatic nerve. Passive dorsiflexion of 
the foot during the maneuver adds to the stretch. 



While flexion to at least 80° is normally possible 
without causing pain, tight hamstring muscles are a 
source of pain in some patients. The straight leg-raising 
(SLR) test is positive if the maneuver reproduces the 
patient's usual back or limb pain. Eliciting the SLR 
sign in the sitting position may help determine if the 
finding is reproducible. The patient may describe pain 
in the low back, buttocks, posterior thigh, or lower 
leg, but the key feature is reproduction of the patient's 
usual pain. The crossed SLR sign is positive when flex- 
ion of one leg reproduces the pain in the opposite leg 
or buttocks. The crossed SLR sign is less sensitive but 
more specific for disk herniation than the SLR sign. 
The nerve or nerve root lesion is always on the side 
of the pain. The reverse SLR sign is elicited by standing 
the patient next to the examination table and passively 
extending each leg with the knee fully extended. This 
maneuver, which stretches the L2-L4 nerve roots and 
the femoral nerve, is considered positive if the patient's 
usual back or limb pain is reproduced. 

The neurologic examination includes a search for 
focal weakness or muscle atrophy, focal reflex changes, 
diminished sensation in the legs, and signs of spinal 
cord injury. The examiner should be alert to the pos- 
sibility of breakaway weakness, defined as fluctuating 
strength during muscle testing. Breakaway weakness 



may be due to pain or a combination of pain and 
underlying true weakness. Breakaway weakness with- 
out pain is due to lack of effort. In uncertain cases, 
electromyography (EMG) can determine whether or 
not true weakness is present. Findings with specific 
nerve root lesions are shown in Table 7-2 and are 
discussed below. 

LABORATORY, IMAGING, AND EMG STUDIES 

Routine laboratory studies are rarely needed for the 
initial evaluation of nonspecific acute (<3 months 
duration) low back pain (ALBP) . If risk factors for a 
serious underlying cause are present, then laboratory 
studies [complete blood count (CBC), erythrocyte 
sedimentation rate (ESR), urinalysis] are indicated. 

CT scanning is superior to routine x-rays for the 
detection of fractures involving posterior spine struc- 
tures, craniocervical and craniothoracic junctions, CI 
and C2 vertebrae, bone fragments within the spinal 
canal, or malalignment; CT scans are increasingly used 
as a primary screening modality for moderate to severe 
trauma. In the absence of risk factors, these imaging 
studies are rarely helpful in nonspecific ALBP. MRI 
and CT-myelography are the radiologic tests of choice 
for evaluation of most serious diseases involving the 
spine. MRI is superior for the definition of soft tissue 



73 



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TABLE 7-2 



LUMBOSACRAL RADICULOPATHY— NEUROLOGIC FEATURES 



EXAMINATION FINDINGS 



LUMBOSACRAL 








PAIN 


NERVE ROOTS 


REFLEX 


SENSORY 


MOTOR 


DISTRIBUTION 


L2 a 


— 


Upper anterior thigh 


Psoas (hip flexion) 


Anterior thigh 


L3 a 




Lower anterior thigh 
Anterior knee 


Psoas (hip flexion) 
Quadriceps (knee extension) 
Thigh adduction 


Anterior thigh, knee 


L4 a 


Quadriceps 
(knee) 


Medial calf 


Quadriceps (knee extension) 6 
Thigh adduction 
Tibialis anterior (foot 
dorsiflexion) 


Knee, medial calf 
Anterolateral thigh 


L5 C 


— 


Dorsal surface — foot 


Peroneii (foot eversion)" 


Lateral calf, dorsal foot, 






Lateral calf 


Tibialis anterior (foot 

dorsiflexion) 
Gluteus medius (hip 

abduction) 
Toe dorsiflexors 


posterolateral thigh, buttocks 


S1 c 


Gastrocnemius/ 


Plantar surface — foot 


Gastrocnemius/soleus (foot 


Bottom foot, posterior calf, 




soleus (ankle) 


Lateral aspect — foot 


plantar flexion)" 
Abductor hallucis (toe 

flexors)" 
Gluteus maximus (hip 

extension) 


posterior thigh, buttocks 



a Reverse straight leg-raising sign present — see "Examination of the Back." 
These muscles receive the majority of innervation from this root. 
c Straight leg-raising sign present — see "Examination of the Back." 



74 



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10 



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structures, whereas CT-myelography provides optimal 
imaging of the lateral recess of the spinal canal and 
bony lesions and is tolerated by claustrophobic 
patients. While the added diagnostic value of modern 
neuroimaging is significant, there is concern that 
these studies may be overutilized in patients with 
ALBP. 

Electrodiagnostic studies can be used to assess the 
functional integrity of the peripheral nervous system 
(Chap. 3). Sensory nerve conduction studies are nor- 
mal when focal sensory loss is due to nerve root 
damage because the nerve roots are proximal to the 
nerve cell bodies in the dorsal root ganglia. The diag- 
nostic yield of needle EMG is higher than that of 
nerve conduction studies for radiculopathy. Denerva- 
tion changes in a myotomal (segmental) distribution 
are detected by sampling multiple muscles supplied 
by different nerve roots and nerves; the pattern of 
muscle involvement indicates the nerve root(s) 
responsible for the injury. Needle EMG provides 
objective information about motor nerve fiber injury 
when the clinical evaluation of weakness is limited by 
pain or poor effort. EMG and nerve conduction 
studies will be normal when only limb pain or sen- 
sory nerve root injury or irritation is present. 



CAUSES OF BACK PAIN (Table 7-3) 

CONGENITAL ANOMALIES OF THE 
LUMBAR SPINE 

Spondylolysis is a bony defect in the pars interarticularis 
(a segment near the junction of the pedicle with the 
lamina) of the vertebra; the etiology may be a stress frac- 
ture in a congenitally abnormal segment. The defect 
(usually bilateral) is best visualized on oblique projec- 
tions in plain x-rays, CT scan, or single photon emission 
CT (SPECT) bone scan and occurs in the setting of a 
single injury, repeated minor injuries, or growth. 
Although frequently asymptomatic, it is the most com- 
mon cause of persistent low back pain in adolescents 
and is often activity-related. 

Spondylolisthesis is the anterior slippage of the verte- 
bral body, pedicles, and superior articular facets, leaving 
the posterior elements behind. Spondylolisthesis can be 
associated with spondylolysis, congenital anomalies of 
the lumbosacral junction, infection, osteoporosis, tumor, 
trauma, prior surgery, or degenerative spine disease. It 
occurs more frequently in women. The slippage may be 
asymptomatic or may cause low back pain and ham- 
string tightness, nerve root injury (the L5 root most fre- 
quently), or symptomatic spinal stenosis. Tenderness may 
be elicited near the segment that has "slipped" forward 
(most often L4 on L5 or occasionally L5 on SI). A "step" 



TABLE 7-3 



CAUSES OF BACK AND NECK PAIN 



Congenital/developmental 

Spondylolysis and spondylolisthesis 3 

Kyphoscoliosis 3 

Spina bifida occulta 3 

Tethered spinal cord 3 
Minor trauma 

Strain or sprain 

Whiplash injury" 
Fractures 

Traumatic — falls, motor vehicle accidents 

Atraumatic — osteoporosis, neoplastic infiltration, 
exogenous steroids 
Intervertebral disk herniation 
Degenerative 

Disk-osteophyte complex 

Internal disk disruption 

Spinal stenosis with neurogenic claudication 3 

Uncovertebral joint disease" 

Atlantoaxial joint disease (e.g., rheumatoid arthritis) 3 
Arthritis 

Spondylosis 

Facet or sacroiliac arthropathy 

Autoimmune (e.g., anklyosing spondylitis, Reiter's 
syndrome) 
Neoplasms — metastatic, hematologic, primary bone 
tumors 
Infection/inflammation 

Vertebral osteomyelitis 

Spinal epidural abscess 

Septic disk 

Meningitis 

Lumbar arachnoiditis 3 
Metabolic 

Osteoporosis — hyperparathyroidism, immobility 

Osteosclerosis (e.g., Paget's disease) 
Vascular 

Abdominal aortic aneurysm 

Vertebral artery dissection'' 
Other 

Referred pain from visceral disease 

Postural 

Psychiatric, malingering, chronic pain syndromes 



a Low back pain only. 
b Neck pain only. 



may be present on deep palpation of the posterior ele- 
ments of the segment above the spondylolisthetic joint. 
The trunk may be shortened and the abdomen protu- 
berant as a result of extreme forward displacement of L4 
on L5; in severe cases cauda equina syndrome (CES) 
may occur (see later). Surgery is considered for symp- 
toms persisting for >1 year that do not respond to con- 
servative measures (e.g., rest, physical therapy). Surgery is 
usually indicated for cases with progressive neurologic 
deficit, abnormal gait or postural deformity, slippage 
>50%, or scoliosis. 



Spina bifida occulta is a failure of closure of one or sev- 
eral vertebral arches posteriorly; the meninges and spinal 
cord are normal. A dimple or small lipoma may overlie 
the defect. Most cases are asymptomatic and discovered 
incidentally during evaluation for back pain. 

Tethered cord syndrome usually presents as a progressive 
cauda equina disorder (see later), although myelopathy 
may also be the initial manifestation. The patient is often 
a young adult who complains of perineal or perianal 
pain, sometimes following minor trauma. Neuroimaging 
studies reveal a low-lying conus (below L1-L2) and a 
short and thickened filum terminale. 

TRAUMA 

A patient with a complaint of back pain and inability to 
move the legs may have a spinal fracture or dislocation, 
and, with fractures above LI, spinal cord compression. 
Care must be taken to avoid further damage to the 
spinal cord or nerve roots by immobilizing the back 
pending results of x-rays. 

Sprains and Strains 

The terms low back sprain, strain, or mechanically induced 
muscle spasm refer to minor, self-limited injuries associ- 
ated with lifting a heavy object, a fall, or a sudden decel- 
eration such as in an automobile accident. These terms 
are used loosely and do not clearly describe a specific 
anatomic lesion. The pain is usually confined to the 
lower back, and there is no radiation to the buttocks or 
legs. Patients with paraspinal muscle spasm often assume 
unusual postures. 

Traumatic Vertebral Fractures 

Most traumatic fractures of the lumbar vertebral bodies 
result from injuries producing anterior wedging or 
compression. With severe trauma, the patient may sustain 
a fracture-dislocation or a "burst" fracture involving the 
vertebral body and posterior elements. Traumatic verte- 
bral fractures are caused by falls from a height (a pars 
interarticularis fracture of the L5 vertebra is common), 
sudden deceleration in an automobile accident, or direct 
injury. Neurologic impairment is common, and early 
surgical treatment is indicated. In victims of blunt 
trauma, CT scans of the chest, abdomen, or pelvis can 
be reformatted to detect associated vertebral fractures. 

LUMBAR DISK DISEASE 

This is a common cause of chronic or recurrent low 
back and leg pain (Figs. 7-3 and 7-4). Disk disease is 
most likely to occur at the L4-L5 and L5-S1 levels, but 
upper lumbar levels are involved occasionally. The cause 
is often unknown; the risk is increased in overweight 




75 



FIGURE 7-4 

MRI of lumbar herniated disk; left S1 radiculopathy. Sagit- 
tal T1 -weighted image on the left with arrows outlining disk 
margins. Sagittal T2 image on the right reveals a protruding 
disk at the L5-S1 level (arrows), which displaces the central 
thecal sac. 



individuals. Disk herniation is unusual prior to age 20 
and is rare in the fibrotic disks of the elderly. Degenera- 
tion of the nucleus pulposus and the annulus fibrosus 
increases with age and may be asymptomatic or painful. 
Genetic factors may play a role in predisposing some 
patients to disk degeneration. The pain may be located 
in the low back only or referred to the leg, buttock, or 
hip. A sneeze, cough, or trivial movement may cause the 
nucleus pulposus to prolapse, pushing the frayed and 
weakened annulus posteriorly. With severe disk disease, 
the nucleus may protrude through the annulus (hernia- 
tion) or become extruded to lie as a free fragment in the 
spinal canal. 

The mechanism by which intervertebral disk injury 
causes back pain is controversial. The inner annulus 
fibrosus and nucleus pulposus are normally devoid of 
innervation. Inflammation and production of proinflam- 
matory cytokines within the protruding or ruptured 
disk may trigger or perpetuate back pain. Ingrowth of 
nociceptive (pain) nerve fibers into inner portions of a 
diseased disk may be responsible for chronic "disko- 
genic" pain. Nerve root injury (radiculopathy) from disk 
herniation may be due to compression, inflammation, or 
both; pathologically, demyelination and axonal loss are 
usually present. 

Symptoms of a ruptured disk include back pain, 
abnormal posture, limitation of spine motion (particu- 
larly flexion), or radicular pain. A dermatomal pattern of 
sensory loss or a reduced or absent deep tendon reflex is 
more suggestive of a specific root lesion than is the pat- 
tern of pain. Motor findings (focal weakness, muscle 



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76 atrophy, or fasciculations) occur less frequently than 
focal sensory or reflex changes. Symptoms and signs are 
usually unilateral, but bilateral involvement does occur 
with large central disk herniations that compress multi- 
ple descending nerve roots within the spinal canal. Clin- 
ical manifestations of specific nerve root lesions are 
summarized in Table 7-2. There is suggestive evidence 
that lumbar disk herniation with a nonprogressive nerve 
root deficit can be managed nonsurgically The size of 
the disk protrusion may naturally decrease over time. 

The differential diagnosis covers a variety of serious 
and treatable conditions, including epidural abscess, 
hematoma, or tumor. Fever, constant pain uninfluenced 
by position, sphincter abnormalities, or signs of spinal 
cord disease suggests an etiology other than lumbar disk 
disease. Bilateral absence of ankle reflexes can be a nor- 
mal finding in old age or a sign of bilateral SI radicu- 
lopathy. An absent deep tendon reflex or focal sensory 
loss may indicate injury to a nerve root, but other sites 
of injury along the nerve must also be considered. For 
example, an absent knee reflex may be due to a femoral 
neuropathy or an L4 nerve root injury. A loss of sensa- 
tion over the foot and lateral lower calf may result from 
a peroneal or lateral sciatic neuropathy or an L5 nerve 
root injury. Focal muscle atrophy may reflect a nerve 
root or peripheral nerve injury, an anterior horn cell 
disease, or disuse. 

An MRI scan or CT-myelogram is necessary to estab- 
lish the location and type of pathology. Spinal MRI yields 
exquisite views of intraspinal and adjacent soft tissue 
anatomy. Bony lesions of the lateral recess or interverte- 
bral foramen are optimally visualized by CT-myelography 
The correlation of neuroradiologic findings to symptoms, 
particularly pain, is not simple. Contrast-enhancing tears 
in the annulus fibrosus or disk protrusions are widely 
accepted as common sources of back pain; however, 
many studies have found that most asymptomatic adults 
have similar findings. Asymptomatic disk protrusions are 
also common and may enhance with contrast. Further- 
more, in patients with known disk herniation treated 
either medically or surgically, persistence of the hernia- 
tion 10 years later had no relationship to the clinical 
outcome. In summary, MRI findings of disk protrusion, 
tears in the annulus fibrosus, or contrast enhancement 
are common incidental findings that, by themselves, 
should not dictate management decisions for patients 
with back pain. 

There are four indications for intervertebral disk 
surgery: (1) progressive motor weakness from nerve root 
injury demonstrated on clinical examination or EMG, 
(2) bowel or bladder disturbance or other signs of spinal 
cord compression, (3) incapacitating nerve root pain 
despite conservative treatment for 4 weeks at a mini- 
mum, and (4) recurrent incapacitating pain despite con- 
servative treatment. The latter two criteria are more sub- 
jective and less well established than the others. Surgical 



treatment should also be considered if steady pain 
and/or neurologic findings do not substantially improve 
over 4—12 weeks. 

The usual surgical procedure is a partial hemil- 
aminectomy with excision of the prolapsed disk. Fusion 
of the involved lumbar segments should be considered 
only if significant spinal instability is present (i.e., degen- 
erative spondylolisthesis or isthmic spondylolysis). Over 
a recent 5-year period, the number of lumbar fusion 
procedures performed in the United States more than 
doubled, for uncertain reasons. There are no large 
prospective, randomized trials comparing fusion to other 
types of surgical intervention. In one study, patients with 
persistent low back pain despite an initial diskectomy 
fared no better with spine fusion than with a conserva- 
tive regimen of cognitive intervention and exercise. 

Cauda equina syndrome (CES) signifies an injury of 
multiple lumbosacral nerve roots within the spinal canal. 
Low back pain, weakness and areflexia in the legs, saddle 
anesthesia, and loss of bladder function may occur. The 
problem must be distinguished from disorders of the lower 
spinal cord (conus medullaris syndrome), acute transverse 
myelitis (Chap. 30), and Guillain-Barre syndrome (Chap. 41). 
Combined involvement of the conus medullaris and 
cauda equina can occur. CES is commonly due to a 
ruptured lumbosacral intervertebral disk, lumbosacral 
spine fracture, hematoma within the spinal canal (e.g., 
following lumbar puncture in patients with coagulopa- 
thy), compressive tumor, or other mass lesion. Treatment 
options include surgical decompression, sometimes 
urgently in an attempt to restore or preserve motor or 
sphincter function, or radiotherapy for metastatic tumors 
(Chap. 32). 

DEGENERATIVE CONDITIONS 

Lumbar spinal stenosis describes a narrowed lumbar spinal 
canal. Neurogenic claudication is the usual symptom, con- 
sisting of back and buttock or leg pain induced by walk- 
ing or standing and relieved by sitting. Symptoms in the 
legs are usually bilateral. Lumbar stenosis, by itself, is fre- 
quently asymptomatic, and the correlation between the 
severity of symptoms and degree of stenosis of the spinal 
canal is poor. Unlike vascular claudication, symptoms are 
often provoked by standing without walking. Unlike lum- 
bar disk disease, symptoms are usually relieved by sitting. 
Focal weakness, sensory loss, or reflex changes may occur 
when spinal stenosis is associated with radiculopathy. 
Severe neurologic deficits, including paralysis and uri- 
nary incontinence, occur rarely. Spinal stenosis can be 
acquired (75%), congenital, or due to a combination of 
these factors. Congenital forms (achondroplasia, idio- 
pathic) are characterized by short, thick pedicles that pro- 
duce both spinal canal and lateral recess stenosis. Acquired 
factors that contribute to spinal stenosis include degenera- 
tive diseases (spondylosis, spondylolisthesis, scoliosis), trauma, 




A B 

FIGURE 7-5 

Spinal stenosis. Sagittal T2 fast spin echo magnetic reso- 
nance imaging of a normal (A) and stenotic (S) lumbar spine, 
revealing multifocal narrowing (arrows) of the cerebrospinal 
fluid spaces surrounding the nerve roots within the thecal sac. 



spine surgery, metabolic or endocrine disorders (epidural 
lipomatosis, osteoporosis, acromegaly, renal osteodystro- 
phy, hypoparathyroidism), and Paget 's disease. MRI 
provides the best definition of the abnormal anatomy 
(Fig. 7-5). 

Conservative treatment of symptomatic spinal steno- 
sis includes nonsteroidal anti-inflammatory drugs 
(NSAIDs), exercise programs, and symptomatic treat- 
ment of acute pain episodes. Surgical therapy is consid- 
ered when medical therapy does not relieve symptoms 
sufficiently to allow for activities of daily living or when 
significant focal neurologic signs are present. Most 
patients with neurogenic claudication treated surgically 
experience at least 75% relief of back and leg pain. Up 
to 25% develop recurrent stenosis at the same spinal 
level or an adjacent level 5 years after the initial surgery; 
recurrent symptoms usually respond to a second surgical 
decompression. 

Facet joint hypertrophy can produce unilateral radicular 
symptoms or signs due to bony compression; symptoms 
are often indistinguishable from disk-related radiculopa- 
thy. Stretch signs, focal motor weakness, hyporeflexia, or 
dermatomal sensory loss may be present. Hypertrophic 
superior or inferior facets can be visualized by x-rays, 
CT, or MRI. Surgical foraminotomy results in long- 
term relief of leg and back pain in 80—90% of these 
patients. The usefulness of therapeutic facet joint blocks 
for pain has not been rigorously studied. 

ARTHRITIS 

Spondylosis, or osteoarthritic spine disease, typically 
occurs in later life and primarily involves the cervical 
and lumbosacral spine. Patients often complain of back 
pain that is increased -with movement and associated 



with stiffness. The relationship between clinical symp- 
toms and radiologic findings is usually not straightfor- 
ward. Pain may be prominent when x-ray, CT, or MRI 
findings are minimal, and large osteophytes can be seen 
in asymptomatic patients. Radiculopathy occurs when 
hypertrophied facets and osteophytes compress nerve 
roots in the lateral recess or intervertebral foramen. 
Osteophytes arising from the vertebral body may cause 
or contribute to central spinal canal stenosis. Disc 
degeneration may also play a role in reducing the cross- 
sectional area of the intervertebral foramen; the 
descending pedicle may compress the exiting nerve 
root. Rarely, osteoarthritic changes in the lumbar spine 
are sufficient to compress the cauda equina. 

Ankylosing Spondylitis 

This distinctive arthritic spine disease typically presents 
with the insidious onset of low back and buttock pain. 
Patients are often males below age 40. Associated fea- 
tures include morning back stiffness, nocturnal pain, 
pain unrelieved by rest, an elevated ESR, and the histo- 
compatibility antigen HLA-B27. Onset at a young age 
and back pain improving with exercise are characteristic. 
Loss of the normal lumbar lordosis and exaggeration of 
thoracic kyphosis develop as the disease progresses. 
Inflammation and erosion of the outer fibers of the 
annulus fibrosus at the point of contact with the verte- 
bral body are followed by ossification and bony growth 
that bridges adjacent vertebral bodies and reduces spine 
mobility in all planes. Radiologic hallmarks are periar- 
ticular destructive changes, sclerosis of the sacroiliac 
joints, and bridging of vertebral bodies to produce the 
fused "bamboo spine." 

Stress fractures through the spontaneously ankylosed 
posterior bony elements of the rigid, osteoporotic spine 
may produce focal pain, spinal instability, spinal cord 
compression, or CES. Atlantoaxial subluxation with 
spinal cord compression occasionally occurs. Ankylosis 
of the ribs to the spine and a decrease in the height of 
the thoracic spine may compromise respiratory func- 
tion. For many patients, therapy with anti-tumor necro- 
sis factor agents is effective in reducing disease activity. 
Similar to ankylosing spondylitis, restricted movements 
may accompany Reiter's syndrome, psoriatic arthritis, 
and chronic inflammatory bowel disease. 

NEOPLASMS 

(See Chap. 32) Back pain is the most common neuro- 
logic symptom in patients with systemic cancer and 
may be the presenting symptom. The cause is usually 
vertebral metastases. Metastatic carcinoma (breast, lung, 
prostate, thyroid, kidney, gastrointestinal tract), multiple 
myeloma, and non-Hodgkin's and Hodgkin's lymphomas 
frequently involve the spine. Cancer-related back pain 



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78 tends to be constant, dull, unrelieved by rest, and worse 
at night. By contrast, mechanical low back pain usually 
improves with rest. Plain x-rays may or may not show 
destructive lesions in one or several vertebral bodies 
without disk space involvement. MRI, CT, and CT- 
myelography are the studies of choice when spinal 
metastasis is suspected. MRI is preferred, but the most 
rapidly available procedure is best because the patient's 
condition may worsen quickly. Less than 5% of patients 
who are nonambulatory at the time of diagnosis ever 
regain the ability to walk, thus early diagnosis is crucial. 

INFECTIONS/INFLAMMATION 

Vertebral osteomyelitis is usually caused by staphylococci, 
but other bacteria or tuberculosis (Pott's disease) may be 
responsible. The primary source of infection is usually 
the urinary tract, skin, or lungs. Intravenous drug use is a 
well-recognized risk factor. Whenever pyogenic 
osteomyelitis is found, the possibility of bacterial endo- 
carditis should be considered. Back pain exacerbated by 
motion and unrelieved by rest, spine tenderness over the 
involved spine segment, and an elevated ESR are the 
most common findings in vertebral osteomyelitis. Fever 
or an elevated white blood cell count is found in a 
minority of patients. Plain radiographs may show a nar- 
rowed disk space with erosion of adjacent vertebrae; 
however, these diagnostic changes may take weeks or 
months to appear. MRI and CT are sensitive and spe- 
cific for osteomyelitis; CT may be more readily available 
in emergency settings and better tolerated by some 
patients with severe back pain. 

Spinal epidural abscess (Chap. 30) presents with back 
pain (aggravated by movement or palpation) and fever. 
Signs of nerve root injury or spinal cord compression 
may be present. The abscess may track over multiple 
spinal levels and is best delineated by spine MRI. 

Lumbar adhesive arachnoiditis with radiculopathy is due 
to fibrosis following inflammation within the subarach- 
noid space. The fibrosis results in nerve root adhesions, 
and presents as back and leg pain associated with motor, 
sensory, or reflex changes. Causes of arachnoiditis include 
multiple lumbar operations, chronic spinal infections, 
spinal cord injury, intrathecal hemorrhage, myelography 
(rare), intrathecal injection of glucocorticoids or anes- 
thetics, and foreign bodies. The MRI shows clumped 
nerve roots located centrally or adherent to the dura 
peripherally, or loculations of cerebrospinal fluid within 
the thecal sac. Clumped nerve roots may also occur with 
demyelinating polyneuropathy or neoplastic infiltration. 
Treatment is usually unsatisfactory. Microsurgical lysis of 
adhesions, dorsal rhizotomy, and dorsal root ganglionec- 
tomy have been tried, but outcomes have been poor. 
Dorsal column stimulation for pain relief has produced 
varying results. Epidural injections of glucocorticoids 
have been of limited value. 



METABOLIC CAUSES 
Osteoporosis and Osteosclerosis 

Immobilization or underlying conditions such as osteo- 
malacia, hyperparathyroidism, hyperthyroidism, multiple 
myeloma, metastatic carcinoma, or glucocorticoid use may 
accelerate osteoporosis and weaken the vertebral body, lead- 
ing to compression fractures and pain. The most common 
causes of nontraumatic vertebral body fractures are post- 
menopausal (type 1) or senile (type 2) osteoporosis. Com- 
pression fractures occur in up to half of patients with severe 
osteoporosis, and those who sustain a fracture have a 4.5- 
fold increased risk for recurrence. The sole manifestation of 
a compression fracture may be localized back pain or radic- 
ular pain exacerbated by movement and often reproduced 
by palpation over the spinous process of the affected verte- 
bra. The clinical context, neurologic signs, and x-ray appear- 
ance of the spine establish the diagnosis. Antiresorptive 
drugs including bisphosphonates (e.g., alendronate), trans- 
dermal estrogen, and tamoxifen have been shown to reduce 
the risk of osteoporotic fractures. Fewer than one-third of 
patients with prior compression fractures are adequately 
treated for osteoporosis despite the increased risk for future 
fractures; rates of primary prevention among individuals at 
risk, but without a history of fracture, are even less. Com- 
pression fractures above the midthoracic region suggest 
malignancy; if tumor is suspected, a bone biopsy or diagnos- 
tic search for a primary tumor is indicated. 

Interventions [percutaneous vertebroplasty (PVP), 
kyphoplasty] exist for osteoporotic compression fractures 
associated with debilitating pain. Candidates for PVP have 
midline back pain, palpation tenderness over the spinous 
process of the affected vertebral body, <80% loss of ver- 
tebral body height, and onset of symptoms within the 
prior 4 months. The PVP technique consists of injection 
of polymethylmethacrylate, under fluoroscopic guidance, 
into the affected vertebral body. Kyphoplasty adds the 
inflation of a balloon in the vertebral body prior to 
the injection of cement. Rare complications can include 
extravasation of cement into the epidural space (resulting 
in myelopathy) or fatal pulmonary embolism from migra- 
tion of cement into paraspinal veins. Approximately three- 
quarters of patients who meet selection criteria have 
reported enhanced quality of life. Relief of pain follow- 
ing PVP has also been reported in patients with vertebral 
metastases, myeloma, or hemangiomas. 

Osteosclerosis, an abnormally increased bone density 
often due to Paget's disease, is readily identifiable on 
routine x-ray studies and may or may not produce back 
pain. Spinal cord or nerve root compression may result 
from bony encroachment. 

REFERRED PAIN FROM VISCERAL DISEASE 

Diseases of the thorax, abdomen, or pelvis may refer pain to 
the posterior portion of the spinal segment that innervates 



the diseased organ. Occasionally, back pain may be the first 
and only manifestation. Upper abdominal diseases gener- 
ally refer pain to the lower thoracic or upper lumbar region 
(eighth thoracic to the first and second lumbar vertebrae), 
lower abdominal diseases to the mid-lumbar region (sec- 
ond to fourth lumbar vertebrae), and pelvic diseases to 
the sacral region. Local signs (pain with spine palpation, 
paraspinal muscle spasm) are absent, and little or no pain 
accompanies routine movements of the spine. 



Low Thoracic or Lumbar Pain with 
Abdominal Disease 

Peptic ulcers or tumors of the posterior wall of the 
stomach or duodenum typically produce epigastric pain, 
but midline back or paraspinal pain may occur if 
retroperitoneal extension is present. Fatty foods are 
more likely to induce back pain associated with biliary 
disease. Diseases of the pancreas produce back pain to 
the right of the spine (head of the pancreas involved) or 
to the left (body or tail involved). Pathology in retroperi- 
toneal structures (hemorrhage, tumors, pyelonephritis) 
produces paraspinal pain that radiates to the lower 
abdomen, groin, or anterior thighs. A mass in the iliop- 
soas region often produces unilateral lumbar pain with 
radiation toward the groin, labia, or testicles. The sudden 
appearance of lumbar pain in a patient receiving antico- 
agulants suggests retroperitoneal hemorrhage. 

Isolated low back pain occurs in 15—20% of patients 
with a contained rupture of an AAA. The classic clinical 
triad of abdominal pain, shock, and back pain occurs in 
<20% of patients. Two of these three features are present 
in two-thirds of patients, and hypotension is present in 
half. The typical patient is an elderly male smoker with 
back pain. Frequently, the diagnosis is initially missed 
because the symptoms and signs can be nonspecific. 
Common misdiagnoses include nonspecific back pain, 
diverticulitis, renal colic, sepsis, and myocardial infarction. 
A careful abdominal examination revealing a pulsatile 
mass (present in 50—75% of patients) is an important 
physical finding. Patients with suspected AAA should be 
evaluated with abdominal ultrasound, CT, or MRI. 

Inflammatory bowel disorders (colitis, diverticulitis) or 
cancers of the colon may produce lower abdominal pain, 
midlumbar back pain, or both. The pain may have a belt- 
line distribution around the body. A lesion in the trans- 
verse or proximal descending colon may refer pain to the 
mid or left back at the L2-L3 level. Lesions of the sigmoid 
colon may refer pain to the upper sacral or midline supra- 
pubic regions or left lower quadrant of the abdomen. 

Sacral Pain with Gynecologic 
and Urologic Disease 

Pelvic organs rarely cause low back pain, except for gyne- 
cologic disorders involving the uterosacral ligaments. 



The pain is referred to the sacral region. Endometriosis 
or uterine cancers may invade the uterosacral ligaments. 
Pain associated with endometriosis is typically premen- 
strual and often continues until it merges with men- 
strual pain. Uterine malposition may cause uterosacral 
ligament traction (retroversion, descensus, and prolapse) 
or produce sacral pain after prolonged standing. 

Menstrual pain may be felt in the sacral region. The 
poorly localized, cramping pain can radiate down the 
legs. Pain due to neoplastic infiltration of nerves is typi- 
cally continuous, progressive in severity, and unrelieved 
by rest at night. Less commonly, radiation therapy of 
pelvic tumors may produce sacral pain from late radia- 
tion necrosis of tissue or nerves. Low back pain that 
radiates into one or both thighs is common in the last 
weeks of pregnancy. 

Urologic sources of lumbosacral back pain include 
chronic prostatitis, prostate cancer with spinal metastasis 
(Chap. 32), and diseases of the kidney and ureter. Lesions 
of the bladder and testes do not usually produce back 
pain. Infectious, inflammatory, or neoplastic renal dis- 
eases may produce ipsilateral lumbosacral pain, as can 
renal artery or vein thrombosis. Paraspinal lumbar pain 
may be a symptom of ureteral obstruction due to 
nephrolithiasis. 

OTHER CAUSES OF BACK PAIN 
Postural Back Pain 

There is a group of patients with nonspecific chronic 
low back pain (CLBP) in whom no anatomic lesion can 
be found despite exhaustive investigation. These individ- 
uals complain of vague, diffuse back pain with pro- 
longed sitting or standing that is relieved by rest. The 
physical examination is unrevealing except for "poor 
posture." Imaging studies and laboratory evaluations do 
not identify a specific cause. Exercises to strengthen the 
paraspinal and abdominal muscles are sometimes helpful. 

Psychiatric Disease 

CLBP may be encountered in patients who seek finan- 
cial compensation; in malingerers; or in those with con- 
current substance abuse, chronic anxiety states, or 
depression. Many patients with CLBP have a history of 
psychiatric illness (depression, anxiety, substance abuse) 
or childhood trauma (physical or sexual abuse) that 
antedates the onset of back pain. Preoperative psycho- 
logical assessment has been used to exclude patients 
with marked psychological impairments that predict a 
poor surgical outcome. 

Unidentified 

The cause of low back pain occasionally remains unclear. 
Some patients have had multiple operations for disk 



79 



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80 disease but have persistent pain and disability. The origi- 
nal indications for surgery may have been questionable, 
with back pain only, no definite neurologic signs, or a 
minor disk bulge noted on CT or MRI. Scoring sys- 
tems based upon neurologic signs, psychological factors, 
physiologic studies, and imaging studies have been devised 
to minimize the likelihood of unsuccessful surgery. 



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Treatment: 
BACK PAIN 



ACUTE LOW BACK PAIN (ALBP) ALBP is 
defined as pain of <3 months' duration. Full recovery can 
be expected in 85% of adults with ALBP without leg 
pain. Most have purely "mechanical" symptoms (i.e., pain 
that is aggravated by motion and relieved by rest). 

Observational studies have been used to justify a 
minimalist approach to this problem. These studies 
share a number of limitations: (1) a true placebo control 
group is often lacking; (2) patients who consult different 
provider groups (generalists, orthopedists, neurologists) 
are assumed to have similar etiologies for their back 
pain; (3) no information is provided about the details of 
treatment; and (4) no attempt to tabulate structural 
causes of ALBP is made. 

The algorithms for the treatment of back pain 
(Fig. 7-6) draw from published clinical practice guide- 
lines (CPGs). However, since CPGs are based on incom- 
plete evidence, guidelines should not substitute for clin- 
ical judgment. 

The initial assessment excludes serious causes of 
spine pathology that require urgent intervention, includ- 
ing infection, cancer, and trauma. Risk factors for a seri- 
ous cause of ALBP are shown in Table 7-1. Laboratory 
studies are unnecessary if risk factors are absent. Plain 
spine films or CT are rarely indicated in the first month of 
symptoms unless a spine fracture is suspected. 

Clinical trials have shown no benefit of >2 days of 
bed rest for uncomplicated ALBP. There is evidence that 
bed rest is also ineffective for patients with sciatica or 
for acute back pain with signs of nerve root injury. Simi- 
larly, traction is not effective for ALBP. Possible advan- 
tages of early ambulation for ALBP include maintenance 
of cardiovascular conditioning, improved disk and carti- 
lage nutrition, improved bone and muscle strength, and 
increased endorphin levels. One trial of early vigorous 
exercise was negative, but the value of less vigorous 
exercise or other exercise programs are unknown. Early 
resumption of normal physical activity (without heavy 
manual labor) is likely to be beneficial. 

Proof is lacking to support the treatment of acute 
back and neck pain with acupuncture, transcutaneous 
electrical nerve stimulation, massage, ultrasound, 
diathermy, magnets, or electrical stimulation. Cervical 



collars can be modestly helpful by limiting spontaneous 
and reflex neck movements that exacerbate pain. Evi- 
dence regarding the efficacy of ice is lacking; heat may 
provide a short-term reduction in pain and disability. 
These interventions are optional given the lack of nega- 
tive evidence, low cost, and low risk. Biofeedback has 
not been studied rigorously. Facet joint, trigger point, 
and ligament injections are not recommended for acute 
treatment. 

A role for modification of posture has not been vali- 
dated by rigorous clinical studies. As a practical matter, 
temporary suspension of activity known to increase 
mechanical stress on the spine (heavy lifting, prolonged 
sitting, bending or twisting, straining at stool) may be 
helpful. 

Education is an important part of treatment. Satisfac- 
tion and the likelihood of follow-up increase when 
patients are educated about prognosis, treatment 
methods, activity modifications, and strategies to pre- 
vent future exacerbations. In one study, patients who 
felt they did not receive an adequate explanation for 
their symptoms wanted further diagnostic tests. Evi- 
dence for the efficacy of structured education programs 
("back school") is inconclusive; there is modest evidence 
for a short-term benefit, but evidence for a long-term 
benefit is lacking. Randomized studies of back school 
for primary prevention of low back injury and pain have 
failed to demonstrate any benefit. 

NSAIDs and acetaminophen (Table 5-1) are effective 
over-the-counter agents for ALBP. Muscle relaxants 
(cyclobenzaprine, 10 mg PO qhs as initial dose, up to 
10 mg PO tid) provide short-term (4-7 days) benefit, 
particularly at night if sleep is affected, but drowsiness 
limits daytime use. Opioid analgesics are no more effec- 
tive than NSAIDs or acetaminophen for initial treatment 
of ALBP, nor do they increase the likelihood of return to 
work. Short-term use of opioids may be necessary in 
patients unresponsive to or intolerant of acetaminophen 
or NSAIDs. There is no evidence to support the use of 
oral glucocorticoids or tricyclic antidepressants for 
ALBP. 

Epidural glucocorticoids may occasionally produce 
short-term pain relief in ALBP with radiculopathy, but 
proof is lacking for pain relief beyond 1 month. Epidural 
glucocorticoids, anesthetics, or opioids are not indicated 
in the initial treatment of ALBP without radiculopathy. 
Diagnostic nerve root blocks have been advocated to 
determine if pain originates from a specific nerve root. 
However, improvement may result even when the nerve 
root is not responsible for the pain; this may occur as a 
placebo effect, from a pain-generating lesion located 
distally along the peripheral nerve, or from anesthesia 
of the sinuvertebral nerve. Therapeutic nerve root 
blocks with injection of glucocorticoids and a local 
anesthetic should be considered only after conservative 



Acute low back +/- leg symptoms 



Medical history and examination 
Risk factors for serious etiology? 



<§> 



<nS> 



Table 7-1 and 7-3 



No diagnostic tests 
Reassurance 
Patient education 
Pain relief necessary? 



<Sto> 



KYte?)- 



Follow-up at 2 weeks 
Return to normal activity? 



<No> 



Symptomatic treatment options 

Encourage early return to usual activity, excluding 
heavy manual labor 
Activity alterations to minimize symptoms 
Acetaminophen or NSAIDs 
Short duration muscle relaxants or opioids optional 
Bed rest optional — no more than 2 days 
Spinal manipulation optional 
Physical therapy optional 



Resume normal activity 



Follow-up at 2 weeks 
Return to activity tolerance? 



Review response to initial treatment 

Review risk factors 

Modify symptomatic treatment 



-® — l 



Resume normal activity 



Follow-up 2 weeks later 
Return to normal activity? 



Algorithm B 











Acute low back pain — Not improving over >4 weeks 
Leg symptoms? 





81 



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<N?> 



Consult specialist; 
neurologic examination 
Clear nerve root signs? 



EMG/NCV 
Radiculopathy? 




Risk factors for 
serious etiology? 



Imaging study (MRI, or 

CT-myelography) 
Are imaging and neurologic 

evaluations concordant? 




Specialist 
follow-up; nerve 
root, plexus, 
or CNS problem? 



Consult spine surgeon 
Algorithm C 




Evaluate 
and treat 



Appropriate 
intervention 



© 
Reconsider symptomatic treatment options 
Exercise program optional 
Symptoms improving? 



<N°> 



By 12 weeks: Address psychosocial issues 
Consider long-term management options 
Consider re-evaluation 



Resume 
normal 
activity 






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QJ 



Back and leg pain managed > 4 weeks 
Focal neurologic deficit by examination or EMG 
Focal pathology by spine imaging study 
Patient symptoms worse or not improving 
Will patient consider surgery? 



— 



<N°> 



Spine surgery consultation to discuss: 
Surgical procedure 
Risks/benefits 

Short-term and long-term outcomes 
Availability of second opinion 
Does the patient choose surgery? 



Algorithm B at © 



Enter Algorithm B at ©postoperatively 



FIGURE 7-6 

Algorithms for management of acute low back pain, age 
>18 years. A. Symptoms <3 months, first 4 weeks. B. Man- 
agement weeks 4-12. CD, entry point from Algorithm C post- 
operatively or if patient declines surgery. C. Surgical options. 
(NSAIDs, nonsteroidal anti-inflammatory drugs; CBC, complete 



blood count; ESR, erythrocyte sedimentation rate; UA, urinal- 
ysis; EMG, electromyography; NCV, nerve conduction velocity 
studies; MRI, magnetic resonance imaging; CT, computed 
tomography; CNS, central nervous system.) 



measures fail, particularly when temporary relief of pain 
is necessary. 

A short course of lumbar spinal manipulation or 
physical therapy (PT) for symptomatic relief of uncom- 
plicated ALBP is a reasonable option. Prospective, ran- 
domized studies are difficult to perform in part because 
there is no consensus about what constitutes an 



adequate placebo control. Specific PT or chiropractic 
protocols that may provide benefit have not been fully 
denned. 

CHRONIC LOW BACK PAIN CLBP, defined as 
pain lasting >12 weeks, accounts for 50% of total back 
pain costs. Risk factors include obesity, female gender, 



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older age, prior history of back pain, restricted spinal 
mobility, pain radiating into a leg, high levels of psycho- 
logical distress, poor self-rated health, minimal physical 
activity, smoking, job dissatisfaction, and widespread 
pain. Combinations of these premorbid factors have 
been used to predict which individuals with ALBP are 
likely to develop CLBP. The initial approach to these 
patients is similar to that for ALBP. Treatment of this het- 
erogeneous group of patients is directed toward the 
underlying cause when known; the ultimate goal is to 
restore function to the maximum extent possible. 

Many conditions that produce CLBP can be identified 
by a combination of neuroimaging and electrophysio- 
logic studies. Spine MRI and CT-myelography are almost 
always the imaging techniques of choice. Imaging stud- 
ies should be performed only in circumstances when 
the results are likely to influence management. 

Injection studies can be used diagnostically to 
help determine the anatomic source of back pain. 
Reproduction of the patient's typical pain with 
diskography has been used as evidence that a spe- 
cific disk is the pain generator. Pain relief following a 
foraminal nerve root block or glucocorticoid injection 
into a facet has been similarly used as evidence that 
the facet joint or nerve root is the source. However, 
the possibility that the injection response was a 
placebo effect or due to systemic absorption of the 
glucocorticoids is usually not considered. The value of 
these procedures in the treatment of CLBP or in the 
selection of candidates for surgery is largely unknown 
despite their widespread use. The value of thermog- 
raphy in the assessment of radiculopathy also has not 
been rigorously studied. 

The diagnosis of nerve root injury is most secure 
when the history, examination, results of imaging 
studies, and the EMG are concordant. The correlation 
between CT and EMG for localization of nerve root injury 
is between 65 and 73%. Up to one-third of asympto- 
matic adults have a disk protrusion detected by CT or 
MRI scans.Thus, surgical intervention based solely upon 
radiologic findings increases the likelihood of an unsuc- 
cessful outcome. 

An unblinded study in patients with chronic sciatica 
found that surgery could hasten relief of symptoms by 
~2 months; however, at 1 year there was no advantage 
of surgery over conservative medical therapy, and 
nearly all patients (95%) in both groups made a full 
recovery regardless of the treatment approach. A large 
observational cohort study of patients with lumbar 
spinal stenosis showed surgery to be relatively safe, 
likely reducing pain at 2 years with little effect on func- 
tion or disability. 

CLBP can be treated with a variety of conservative 
measures. Acute and subacute exacerbations are man- 
aged with NSAIDs and comfort measures. There is no 



good evidence to suggest that one NSAID is more 
effective than another. Bed rest should not exceed 
2 days. Activity tolerance is the primary goal, while 
pain relief is secondary. Exercise programs can reverse 
atrophy in paraspinal muscles and strengthen exten- 
sors of the trunk. Intensive physical exercise or "work 
hardening" regimens (under the guidance of a physical 
therapist) have been effective in returning some patients 
to work, improving walking distances, and diminishing 
pain. The benefit can be sustained with home exercise 
regimens. It is difficult to endorse one specific exercise 
or PT regimen given the heterogeneous nature of this 
patient group. The role of manipulation, back school, 
or epidural steroid injections in the treatment of CLBP 
is unproven. There is no strong evidence to support 
the use of acupuncture or traction. A reduction in sick 
leave days, long-term health care utilization, and pen- 
sion expenditures may offset the initial expense of 
multidisciplinary treatment programs. Studies of 
hydrotherapy for CLBP have yielded mixed results; 
however, given its low risk and cost, hydrotherapy can 
be considered as a treatment option. Transcutaneous 
electrical nerve stimulation (TENS) has not been ade- 
quately studied in CLBP. 



PAIN IN THE NECK AND SHOULDER 

Neck pain, which usually arises from diseases of the cer- 
vical spine and soft tissues of the neck, is common (4.6% 
of adults in one study) . Neck pain arising from the cer- 
vical spine is typically precipitated by movement and 
may be accompanied by focal tenderness and limitation 
of motion. Pain arising from the brachial plexus, shoul- 
der, or peripheral nerves can be confused with cervical 
spine disease, but the history and examination usually 
identify a more distal origin for the pain. Cervical spine 
trauma, disk disease, or spondylosis may be asympto- 
matic or painful and can produce a myelopathy, radicu- 
lopathy, or both. The nerve roots most commonly 
affected are C7 and C6. 



TRAUMA TO THE CERVICAL SPINE 

Trauma to the cervical spine (fractures, subluxation) 
places the spinal cord at risk for compression. Motor 
vehicle accidents, violent crimes, or falls account for 87% 
of spinal cord injuries (Chap. 30). Immediate immobi- 
lization of the neck is essential to minimize further spinal 
cord injury from movement of unstable cervical spine 
segments. A CT scan is the diagnostic procedure of 
choice for detection of acute fractures. Following major 



TABLE 7-4 



CERVICAL RADICULOPATHY— NEUROLOGIC FEATURES 



EXAMINATION FINDINGS 



83 



CERVICAL 








PAIN 


NERVE ROOTS 


REFLEX 


SENSORY 


MOTOR 


DISTRIBUTION 


C5 


Biceps 


Over lateral deltoid 


Supraspinatus 3 (initial arm abduction) 
Infraspinatus 3 (arm external rotation) 
Deltoid 3 (arm abduction) 
Biceps (arm flexion) 


Lateral arm, medial scapula 


C6 


Biceps 


Thumb, index fingers 


Biceps (arm flexion) 


Lateral forearm, thumb, 






Radial hand/forearm 


Pronator teres (internal forearm 
rotation) 


index finger 


C7 


Triceps 


Middle fingers 


Triceps 3 (arm extension) 


Posterior arm, dorsal 






Dorsum forearm 


Wrist extensors 3 

Extensor digitorum 3 (finger extension) 


forearm, lateral hand 


C8 


Finger 


Little finger 


Abductor pollicis brevis (abduction D1) 


4th and 5th fingers, medial 




flexors 


Medial hand 
and forearm 


First dorsal interosseous (abduction D2) 
Abductor digiti minimi (abduction D5) 


forearm 


T1 


Finger 


Axilla and 


Abductor pollicis brevis (abduction D1) 


Medial arm, axilla 




flexors 


medial arm 


First dorsal interosseous (abduction D2) 
Abductor digiti minimi (abduction D5) 





a These muscles receive the majority of innervation from this root. 



CD 
CD 

— 

CD 

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trauma to the cervical spine, injury to the vertebral 
arteries is common; most lesions are asymptomatic and 
can be visualized by MRI and angiography. 

Whiplash injury is due to trauma (usually automobile 
accidents) causing cervical musculoligamental sprain or 
strain due to hyperflexion or hyperextension. This diag- 
nosis should not be applied to patients with fractures, 
disk herniation, head injury focal neurologic findings, or 
altered consciousness. Imaging of the cervical spine is 
not cost-effective acutely but is useful to detect disk 
herniations when symptoms persist for >6 weeks fol- 
lowing the injury. Severe initial symptoms have been 
associated with a poor long-term outcome. 

CERVICAL DISK DISEASE 

Herniation of a lower cervical disk is a common cause of 
neck, shoulder, arm, or hand pain or tingling. Neck pain, 
stiffness, and a range of motion limited by pain are the 
usual manifestations. A herniated cervical disk is respon- 
sible for ~25% of cervical radiculopathies. Extension and 
lateral rotation of the neck narrows the ipsilateral inter- 
vertebral foramen and may reproduce radicular symp- 
toms (Spurling's sign). In young persons, acute nerve root 
compression from a ruptured cervical disk is often due to 
trauma. Cervical disk herniations are usually posterolat- 
eral near the lateral recess and intervertebral foramen. 
Typical patterns of reflex, sensory and motor changes 
that accompany specific cervical nerve root lesions are 
summarized in Table 7-4; however, (1) overlap in func- 
tion between adjacent nerve roots is common, (2) symp- 
toms and signs may be evident in only part of the injured 



nerve root territory, and (3) the location of pain is the 
most variable of the clinical features. 



CERVICAL SPONDYLOSIS 

Osteoarthritis of the cervical spine may produce neck 
pain that radiates into the back of the head, shoulders, or 
arms, or may be the source of headaches in the posterior 
occipital region (supplied by the C2-C4 nerve roots). 
Osteophytes, disk protrusions, and hypertrophic facet or 
uncovertebral joints may compress one or several nerve 
roots at the intervertebral foramina (Fig. 7-7); this com- 
pression accounts for 75% of cervical radiculopathies. 
The roots most commonly affected are C7 and C6. 
Narrowing of the spinal canal by osteophytes, ossifica- 
tion of the posterior longitudinal ligament (OPLL), or a 
large central disk may compress the cervical spinal cord. 
Combinations of radiculopathy and myelopathy may 
also be present. Spinal cord involvement is suggested by 
Lhermitt's symptom, an electrical sensation elicited by 
neck flexion and radiating down the spine from the 
neck. When little or no neck pain accompanies cord 
compression, the diagnosis may be confused with amy- 
otrophic lateral sclerosis (Chap. 27), multiple sclerosis 
(Chap. 34), spinal cord tumors, or syringomyelia (Chap. 30). 
The possibility of cervical spondylosis should be consid- 
ered even when the patient presents with symptoms or 
signs in the legs only. MRI is the study of choice to 
define the anatomic abnormalities, but plain CT is ade- 
quate to assess bony spurs, foraminal narrowing, or 
OPLL. EMG and nerve conduction studies can localize 
and assess the severity of the nerve root injury. 



84 



ST 
o' 





FIGURE 7-7 

Cervical spondylosis; left C6 radiculopathy. A. Sagittal T2 fast spin echo 
magnetic resonance imaging reveals a hypointense osteophyte that pro- 
trudes from the C5-C6 level into the thecal sac, displacing the spinal cord 
posteriorly (white arrow). B. Axial 2-mm section from a 3-D volume gradient 
echo sequence of the cervical spine. The high signal of the right C5-C6 
intervertebral foramen contrasts with the narrow high signal of the left 
C5-C6 intervertebral foramen produced by osteophytic spurring (arrows). 



o 
10 



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QJ 



OTHER CAUSES OF NECK PAIN 

Rheumatoid arthritis (RA) of the cervical apophyseal 
joints produces neck pain, stiffness, and limitation of 
motion. In advanced RA, synovitis of the atlantoaxial 
joint (C1-C2; Fig. 7-2) may damage the transverse liga- 
ment of the atlas, producing forward displacement of the 
atlas on the axis (atlantoaxial subluxation). Radiologic 
evidence of atlantoaxial subluxation occurs in 30% of 
patients with RA. Not surprisingly, the degree of sub- 
luxation correlates with the severity of erosive disease. 
When subluxation is present, careful assessment is 
important to identify early signs of myelopathy. Occa- 
sional patients develop high spinal cord compression 
leading to quadriparesis, respiratory insufficiency, and 
death. Surgery should be considered when myelopathy 
or spinal instability is present. 

Ankylosing spondylitis can cause neck pain and less com- 
monly atlantoaxial subluxation; surgery may be required 
to prevent spinal cord compression. Acute herpes zoster 
presents as acute posterior occipital or neck pain prior to 
the outbreak of vesicles. Neoplasms metastatic to the cervi- 
cal spine, infections (osteomyelitis and epidural abscess), and 
metabolic bone diseases may be the cause of neck pain. Neck 
pain may also be referred from the heart with coronary 
artery ischemia (cervical angina syndrome). 



THORACIC OUTLET 

The thoracic outlet contains the first rib, the subclavian 
artery and vein, the brachial plexus, the clavicle, and the 



lung apex. Injury to these structures may result in pos- 
tural or movement-induced pain around the shoulder 
and supraclavicular region. True neurogenic thoracic outlet 
syndrome (TOS) results from compression of the lower 
trunk of the brachial plexus or ventral rami of the C8 or 
Tl nerve roots by an anomalous band of tissue connect- 
ing an elongate transverse process at C7 with the first 
rib. Signs include weakness of intrinsic muscles of the 
hand and diminished sensation on the palmar aspect of 
the fourth and fifth digits. EMG and nerve conduction 
studies confirm the diagnosis. Treatment consists of sur- 
gical resection of the anomalous band. The weakness 
and wasting of intrinsic hand muscles typically does not 
improve, but surgery halts the insidious progression of 
weakness. Arterial TOS results from compression of the 
subclavian artery by a cervical rib; the compression 
results in poststenotic dilatation of the artery and throm- 
bus formation. Blood pressure is reduced in the affected 
limb, and signs of emboli may be present in the hand. 
Neurologic signs are absent. Ultrasound can confirm the 
diagnosis noninvasively Treatment is with thrombolysis 
or anticoagulation (with or without embolectomy) and 
surgical excision of the cervical rib compressing the 
subclavian artery or vein. Disputed TOS includes a large 
number of patients with chronic arm and shoulder pain 
of unclear cause. The lack of sensitive and specific find- 
ings on physical examination or laboratory markers for 
this condition frequently results in diagnostic uncer- 
tainty. The role of surgery in disputed TOS is controver- 
sial. Multidisciplinary pain management is a conservative 
approach, although treatment is often unsuccessful. 



BRACHIAL PLEXUS AND NERVES 

Pain from injury to the brachial plexus or peripheral 
nerves of the arm can occasionally mimic pain of cervi- 
cal spine origin. Neoplastic infiltration of the lower 
trunk of the brachial plexus may produce shoulder pain 
radiating down the arm, numbness of the fourth and 
fifth fingers, and weakness of intrinsic hand muscles 
innervated by the ulnar and median nerves. Postradia- 
tion fibrosis (most commonly from treatment of breast 
cancer) may produce similar findings, although pain is 
less often present. A Pancoast tumor of the lung is 
another cause and should be considered, especially when 
a Horner's syndrome is present. Suprascapular neuropathy 
may produce severe shoulder pain, weakness, and wast- 
ing of the supraspinatous and infraspinatous muscles. 
Acute brachial neuritis is often confused with radiculopa- 
thy; the acute onset of severe shoulder or scapular pain is 
followed over days to weeks by weakness of the proxi- 
mal arm and shoulder girdle muscles innervated by the 
upper brachial plexus. The onset is often preceded by an 
infection. The suprascapular and long thoracic nerves are 
most often affected; the latter results in a winged 
scapula. Brachial neuritis may also present as an isolated 
paralysis of the diaphragm. Complete recovery occurs in 
75% of patients after 2 years and in 89% after 3 years. 

Occasional cases of carpal tunnel syndrome produce 
pain and paresthesias extending into the forearm, arm, 
and shoulder resembling a C5 or C6 root lesion. Lesions 
of the radial or ulnar nerve can mimic a radiculopathy at 
C7 or C8, respectively. EMG and nerve conduction 
studies can accurately localize lesions to the nerve roots, 
brachial plexus, or peripheral nerves. For further discus- 
sion of peripheral nerve disorders, see Chap. 40. 

SHOULDER 

Pain arising from the shoulder can on occasion mimic pain 
from the spine. If symptoms and signs of radiculopathy are 
absent, then the differential diagnosis includes mechanical 
shoulder pain (tendonitis, bursitis, rotator cuff tear, disloca- 
tion, adhesive capsulitis, and cuff impingement under the 
acromion) and referred pain (subdiaphragmatic irritation, 
angina, Pancoast tumor) . Mechanical pain is often worse at 
night, associated with local shoulder tenderness and aggra- 
vated by abduction, internal rotation, or extension of the 
arm. Pain from shoulder disease may radiate into the arm 
or hand, but sensory, motor, and reflex changes are absent. 



D Treatment: 

fy NECK PAIN 

There are few well-designed clinical trials that address 
optimal treatment of neck pain or cervical radiculopa- 
thy. Relief of pain, prevention of recurrence, and 



improved neurologic function are reasonable goals. 
Symptomatic treatment includes the use of analgesic 
medications and/or a soft cervical collar. Most treatment 
recommendations reflect anecdotal experience, case 
series, or conclusions derived from studies of the lumbar 
spine. Controlled studies of oral prednisone or trans- 
foraminal glucocorticoid injections have not been per- 
formed. Reasonable indications for cervical disk surgery 
include a progressive radicular motor deficit, pain that 
fails to respond to conservative management and limits 
activities of daily living, or cervical spinal cord compres- 
sion. Surgical management of herniated cervical disks 
usually consists of an anterior approach with diskec- 
tomy followed by anterior interbody fusion. A simple 
posterior partial laminectomy with diskectomy is an 
acceptable alternative approach. Another surgical 
approach involves implantation of an artificial disk; in 
one prospective trial, outcomes after 2 years favored the 
implant over a traditional anterior cervical discectomy 
with fusion. The artificial disk is not yet approved for 
general use in the United States. The risk of subsequent 
radiculopathy or myelopathy at cervical segments adja- 
cent to the fusion is -3% per year and 26% per decade. 
Although this risk is sometimes portrayed as a late com- 
plication of surgery, it may also reflect the natural his- 
tory of degenerative cervical disk disease. 

Nonprogressive cervical radiculopathy due to a her- 
niated cervical disk may be treated conservatively, even 
if a focal neurologic deficit is present, with a high rate of 
success. However, if the cervical radiculopathy is due to 
bony compression from cervical spondylosis, then surgi- 
cal decompression is generally indicated to forestall the 
progression of neurologic signs. 

Cervical spondylotic myelopathy is typically man- 
aged with either anterior decompression and fusion or 
laminectomy in order to forestall progression of the 
myelopathy known to occur in 20-30% of untreated 
patients. However, one prospective study comparing 
surgery vs. conservative treatment for mild cervical 
spondylotic myelopathy showed no difference in out- 
come after 2 years of follow-up. 



FURTHER READINGS 

Bagley LJ: Imaging of spinal trauma. Radiol Clin North Am 44:1, 2006 

BHANGLE SD et al: Back pain made simple: an approach based on 
principles and evidence. Cleve Clin J Med 76:393, 2009 

CASSIDY JD et al: Effect of eliminating compensation for pain and 
suffering on the outcome of insurance claims for whiplash 
injury. N Engl J Med 342:1179, 2000 

CAVALIER R et al: Spondylolysis and spondylolisthesis in children and 
adolescents: Diagnosis, natural history, and non-surgical manage- 
ment.] Am Acad Orthop Surg 14:417, 2006 

COWAN JA JR et al: Changes in the utilization of spinal fusion in the 
United States. Neurosurgery 59:1, 2006 



85 



CO 
QJ 



QJ 



-o 

QJ 



8< DATTA S et al: Systematic assessment of diagnostic accuray and thera- 
peutic utility of lumbar facet joint interventions. Pain Physician 
12:437, 2009 

MUMMANENI PV et al: Clinical and radiographic analysis of cervi- 
cal disk arthroplasty compared with allograft fusion: A ran- 
domized controlled clinical trial. J Neurosurg Spine 6:198, 
2007 

Peul WC et al: Surgery versus prolonged conservative treatment for 
sciatica. N Engl J Med 356:2245, 2007 



Van Alfen N,Van Engelen BG:The clinical spectrum of neuralgic 

amyotrophy in 246 cases. Brain 129:438,2006 
WEINSTEIN JN et al: Surgical versus nonsurgical therapy for lumbar 

spinal stenosis. N Engl J Med 358:794, 2008 
et al: Surgical versus nonsurgical treatment for lumbar 

degenerative spondylolisthesis. N Engl J Med 356:2257, 2007 
et al: Surgical vs nonoperative treatment for lumbar disc 



herniation. The spine patient outcomes research trial (SPORT): 
A randomized trial. JAMA 296:2441, 2006 



ST 
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o 



CD 
QJ 




Mark D. Carlson 



Pathophysiology 87 

Causes of Syncope 88 

Disorders of Vascular Tone or Blood Volume 88 

Cardiovascular Disorders 90 

Cerebrovascular Disease 91 

Differential Diagnosis 91 

Anxiety Attacks and Hyperventilation Syndrome 91 

Seizures 91 

Hypoglycemia 91 

Hysterical Fainting 91 

Further Readings 95 



Syncope, a transient loss of consciousness and postural tone 
due to reduced cerebral blood flow, is associated with spon- 
taneous recovery. It may occur suddenly, without warning, 
or may be preceded by symptoms of faintness ("presyn- 
cope"). These symptoms include lightheadedness, dizziness, 
a feeling of warmth, diaphoresis, nausea, and visual blurring 
occasionally proceeding to transient blindness. Presyncopal 
symptoms vary in duration and may increase in severity 
until loss of consciousness occurs, or they may resolve prior 
to loss of consciousness if the cerebral ischemia is cor- 
rected. The differentiation of syncope from seizure is an 
important, sometimes difficult, diagnostic problem. 

Syncope may be benign when it occurs as a result of 
normal cardiovascular reflex effects on heart rate and 
vascular tone, or serious when due to a life-threatening 
cardiac arrhythmia. Syncope may occur as a single event 
or may be recurrent. Recurrent, unexplained syncope, 
particularly in an individual with structural heart disease, 
is associated with a high risk of death (40% mortality 
within 2 years) . 

PATHOPHYSIOLOGY 

Under normal circumstances systemic blood pressure is 
regulated by a complex process that includes the mus- 
culature, venous valves, autonomic nervous system, and 



87 



renin-aldosterone-angiotensin system. Knowledge of 
the processes is important to understanding the patho- 
physiology of syncope. Approximately three-fourths of 
the systemic blood volume is contained in the venous 
bed, and any interference in venous return may lead to 
a reduction in cardiac output. Cerebral blood flow can 
be maintained if cardiac output and systemic arterial 
vasoconstriction compensate, but when these adjust- 
ments fail, hypotension with resultant cerebral under- 
perfusion to less than half of normal results in syncope. 
Normally, the pooling of blood in the lower parts of 
the body is prevented by (1) pressor reflexes that 
induce constriction of peripheral arterioles and venules, 
(2) reflex acceleration of the heart by means of aortic 
and carotid reflexes, and (3) improvement of venous 
return to the heart by activity of the muscles of the 
limbs. Tilting a normal person upright on a tilt table 
causes some blood to accumulate in the lower limbs 
and diminishes cardiac output slightly; this may be fol- 
lowed by a slight transitory fall in systolic blood pres- 
sure. However, in a patient with defective vasomotor 
reflexes, upright tilt may produce an abrupt and sustained 
fall in blood pressure, precipitating a faint. A recent 
study suggests that susceptibility to neurally-mediated 
syncope is driven partly by an enhanced vascular response 
to hypocapnia. 



88 



CAUSES OF SYNCOPE 



a> 
ST 
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in 



a> 



Transiently decreased cerebral blood flow is usually due 
to one of three general mechanisms: disorders of vascu- 
lar tone or blood volume, cardiovascular disorders 
including obstructive lesions and cardiac arrhythmias, or 
cerebrovascular disease (Table 8-1). Not infrequently, 
however, the cause of syncope is multifactorial. 



DISORDERS OF VASCULAR TONE OR 
BLOOD VOLUME 

Disorders of vascular tone or blood volume that can 
cause syncope include the reflex syncopes and a number 
of conditions resulting in orthostatic intolerance. The 
reflex syncopes — including neurocardiogenic syncope, 
situational syncope, and carotid sinus hypersensitivity — 
share common autonomic nervous system pathophysio- 
logic mechanisms: a cardioinhibitory component (e.g., 
bradycardia due to increased vagal activity), a vasodepres- 
sor component (e.g., inappropriate vasodilatation due to 
sympathetic withdrawal), or both. 



Neurocardiogenic (Vasovagal and 
Vasodepressor) Syncope 

The term neurocardiogenic is generally used to encompass 
both vasovagal and vasodepressor syncope. Strictly speak- 
ing, vasovagal syncope is associated with both sympathetic 
withdrawal (vasodilatation) and increased parasympa- 
thetic activity (bradycardia), whereas vasodepressor syn- 
cope is associated with sympathetic withdrawal alone. 

These forms of syncope are the common faint that 
may be experienced by normal persons; they account for 
approximately half of all episodes of syncope. Neurocar- 
diogenic syncope is frequently recurrent and commonly 
precipitated by a hot or crowded environment, alcohol, 
extreme fatigue, severe pain, hunger, prolonged standing, 
and emotional or stressful situations. Episodes are often 
preceded by a presyncopal prodrome lasting seconds to 
minutes, and rarely occur in the supine position. The 
individual is usually sitting or standing and experiences 
weakness, nausea, diaphoresis, lightheadedness, blurred 
vision, and often a forceful heartbeat with tachycardia 
followed by cardiac slowing and decreasing blood pres- 
sure prior to loss of consciousness. The individual appears 
pale or ashen; in dark-skinned individuals, the pallor may 
only be notable in the conjunctivae and lips. Patients 
with a gradual onset of presyncopal symptoms have time 
to protect themselves against injury; in others, syncope 
occurs suddenly, without warning. 

The depth and duration of unconsciousness vary. 
Sometimes the patient remains partly aware of the sur- 
roundings, or there may be complete unresponsiveness. 
The unconscious patient usually lies motionless, with 



TABLE 8-1 



CAUSES OF SYNCOPE 



I. Disorders of Vascular Tone or Blood Volume 

A. Reflex syncopes 

1. Neurocardiogenic 

2. Situational 
Cough 
Micturition 
Defecation 
Valsalva 
Deglutition 

3. Carotid sinus hypersensitivity 

B. Orthostatic hypotension 

1 . Drug-induced (antihypertensive or vasodilator 
drugs) 

2. Pure autonomic failure (idiopathic orthostatic 
hypotension) 

3. Multisystem atrophies 

4. Peripheral neuropathy (diabetic, alcoholic, 
nutritional, amyloid) 

5. Physical deconditioning 

6. Sympathectomy 

7. Decreased blood volume 

II. Cardiovascular Disorders 

A. Structural and obstructive causes 



7. 

8. 

9. 

10. 



Pulmonary embolism 

Pulmonary hypertension 

Atrial myxoma 

Mitral valvular stenosis 

Myocardial disease (massive acute myocardial 

infarction) 

Left ventricular myocardial restriction or 

constriction 

Pericardial constriction or tamponade 

Aortic outflow tract obstruction 

Aortic valvular stenosis 

Hypertrophic obstructive cardiomyopathy 



B. Cardiac arrhythmias 

1. Bradyarrhythmias 

a. Sinus bradycardia, sinoatrial block, sinus 
arrest, sick-sinus syndrome 

b. Atrioventricular block 

2. Tachyarrhythmias 

a. Supraventricular tachycardia with structural 
cardiovascular disease 

b. Atrial fibrillation with the Wolff-Parkinson-White 
syndrome 

c. Atrial flutter with 1:1 atrioventricular 
conduction 

d. Ventricular tachycardia 
III. Cerebrovascular Disease 

A. Vertebrobasilar insufficiency 

B. Basilar artery migraine 

IV Other Disorders that May Resemble Syncope 

A. Metabolic 

1. Hypoxia 

2. Anemia 

3. Diminished carbon dioxide due to hyperventilation 

4. Hypoglycemia 

B. Psychogenic 

1 . Anxiety attacks 

2. Hysterical fainting 

C. Seizures 



skeletal muscles relaxed, but a few clonic jerks of the 
limbs and face may occur. Sphincter control is usually 
maintained, in contrast to a seizure. The pulse may be 
feeble or apparently absent, the blood pressure low or 
undetectable, and breathing may be almost impercepti- 
ble. The duration of unconsciousness is rarely longer 
than a few minutes if the conditions that provoke the 
episode are reversed. Once the patient is placed in a 
horizontal position, the strength of the pulse improves, 
color begins to return to the face, breathing becomes 
quicker and deeper, and consciousness is restored. Some 
patients may experience a sense of residual weakness 
after regaining consciousness, and rising too soon may 
precipitate another faint. Unconsciousness may be pro- 
longed if an individual remains upright; thus, it is essen- 
tial that individuals with vasovagal syncope assume a 
recumbent position as soon as possible. Although usually 
benign, neurocardiogenic syncope can be associated 
with prolonged asystole and hypotension, resulting in 
hypoxic-ischemic injury. 

Neurocardiogenic syncope often occurs in the setting 
of increased peripheral sympathetic activity and venous 
pooling. Under these conditions, vigorous myocardial 
contraction of a relatively empty left ventricle is thought 
to activate myocardial mechanoreceptors and vagal affer- 
ent nerve fibers that inhibit sympathetic activity and 
increase parasympathetic activity. The resultant vasodilata- 
tion and bradycardia induce hypotension and syncope. 
Although the reflex involving myocardial mechanore- 
ceptors is the mechanism usually accepted as responsible 
for neurocardiogenic syncope, other reflexes may also be 
operative. Patients with transplanted (denervated) hearts 
have experienced cardiovascular responses identical to 
those present during neurocardiogenic syncope. This 
should not be possible if the response depends solely on 
the reflex mechanisms described above, unless the trans- 
planted heart has become reinnervated. Moreover, neu- 
rocardiogenic syncope often occurs in response to stimuli 
(fear, emotional stress, or pain) that may not be associated 
with venous pooling in the lower extremities, which 
suggests a cerebral component to the reflex. 

As distinct from the peripheral mechanisms, the cen- 
tral nervous system (CNS) mechanisms responsible for 
neurocardiogenic syncope are uncertain, but a sudden 
surge in central serotonin levels may contribute to the 
sympathetic withdrawal. Endogenous opiates (endor- 
phins) and adenosine are also putative participants in the 
pathogenesis. 

Situational Syncope 

A variety of activities, including cough, deglutition, mic- 
turition, and defecation, are associated with syncope in 
susceptible individuals. Like neurocardiogenic syncope, 
these syndromes may involve a cardioinhibitory response, 
a vasodepressor response, or both. Cough, micturition, 



and defecation are associated with maneuvers (such as 
Valsalva's, straining, and coughing) that may contribute 
to hypotension and syncope by decreasing venous 
return. Increased intracranial pressure secondary to the 
increased intrathoracic pressure may also contribute by 
decreasing cerebral blood flow. 

Cough syncope typically occurs in men with chronic 
bronchitis or chronic obstructive lung disease during or 
after prolonged coughing fits. Micturition syncope 
occurs predominantly in middle-aged and older men, 
particularly those with prostatic hypertrophy and 
obstruction of the bladder neck; loss of consciousness 
usually occurs at night during or immediately after 
voiding. Deglutition syncope and defecation syncope 
occur in men and women. Deglutition syncope may be 
associated with esophageal disorders, particularly 
esophageal spasm. In some individuals, particular foods 
and carbonated or cold beverages initiate episodes by 
activating esophageal sensory receptors that trigger 
reflex sinus bradycardia or atrioventricular (AV) block. 
Defecation syncope is probably secondary to Valsalva's 
maneuver in older individuals with constipation. 



Carotid Sinus Hypersensitivity 

Syncope due to carotid sinus hypersensitivity is precipi- 
tated by pressure on the carotid sinus baroreceptors, 
which are located just cephalad to the bifurcation of the 
common carotid artery. This typically occurs in the setting 
of shaving, a tight collar, or turning the head to one side. 
Carotid sinus hypersensitivity occurs predominantly in 
men >50 years. Activation of carotid sinus baroreceptors 
gives rise to impulses carried via the nerve of Hering, a 
branch of the glossopharyngeal nerve, to the medulla in 
the brainstem. These afferent impulses activate efferent 
sympathetic nerve fibers to the heart and blood vessels, 
cardiac vagal efferent nerve fibers, or both. In patients 
with carotid sinus hypersensitivity, these responses may 
cause sinus arrest or AV block (a cardioinhibitory response), 
vasodilatation (a vasodepressor response), or both (a mixed 
response) . The underlying mechanisms responsible for the 
carotid sinus hypersensitivity are not clear, and validated 
diagnostic criteria do not exist. 



Postural (Orthostatic) Hypotension 

Orthostatic intolerance can result from hypovolemia or 
from disturbances in vascular control. The latter may 
occur due to agents that affect the vasculature or due to 
primary or secondary abnormalities of autonomic con- 
trol. Sudden rising from a recumbent position or stand- 
ing quietly are precipitating circumstances. Orthostatic 
hypotension may be the cause of syncope in up to 30% of the 
elderly; polypharmacy with antihypertensive or antidepressant 
drugs is often a contributor in these patients. 



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90 Postural syncope may occur in otherwise normal per- 
sons with defective postural reflexes. Pure autonomic 
failure (formerly called idiopathic postural hypotension) is 
characterized by orthostatic hypotension, syncope and 
near syncope, neurocardiogenic bladder, constipation, 
heat intolerance, inability to sweat, and erectile dysfunc- 
tion (Chap. 28) . The disorder is more common in men 
than women and typically begins between 50 and 75 years 
of age. 

Orthostatic hypotension, often accompanied by distur- 
bances in sweating, impotence, and sphincter difficulties, 
is also a primary feature of a variety or other autonomic 
nervous system disorders (Chap. 28). Among the most 
common causes of neurogenic orthostatic hypotension 
are chronic diseases of the peripheral nervous system 
that involve postganglionic unmyelinated fibers (e.g., 
diabetic, nutritional, and amyloid polyneuropathy). 
Much less common are the multiple system atrophies; 
these are CNS disorders in which orthostatic hypoten- 
sion is associated with (1) parkinsonism (Shy-Drager 
syndrome), (2) progressive cerebellar degeneration, or (3) 
a more variable parkinsonian and cerebellar syndrome 
(Chap. 28). A rare, acute postganglionic dysautonomia may 
represent a variant of Guillain-Barre syndrome (Chaps. 28 
and 41); a related disorder, autoimmune autonomic neu- 
ropathy, is associated with autoantibodies to the ganglionic 
acetylcholine receptor. 

There are several additional causes of postural syn- 
cope: (1) after physical deconditioning (such as after 
prolonged illness with recumbency, especially in elderly 
individuals with reduced muscle tone) or after pro- 
longed weightlessness, as in space flight; (2) after sympa- 
thectomy that has abolished vasopressor reflexes; and (3) 
in patients receiving antihypertensive or vasodilator drugs 
and those who are hypovolemic because of diuretics, 
excessive sweating, diarrhea, vomiting, hemorrhage, or 
adrenal insufficiency. 

Glossopharyngeal Neuralgia 

Syncope due to glossopharyngeal neuralgia (Chap. 29) is 
preceded by pain in the oropharynx, tonsillar fossa, or 
tongue. Loss of consciousness is usually associated with 
asystole rather than vasodilatation. The mechanism is 
thought to involve activation of afferent impulses in the 
glossopharyngeal nerve that terminate in the nucleus 
solitarius of the medulla and, via collaterals, activate the 
dorsal motor nucleus of the vagus nerve. 



CARDIOVASCULAR DISORDERS 

Cardiac syncope results from a sudden reduction in car- 
diac output, caused most commonly by a cardiac arrhyth- 
mia. In normal individuals, heart rates between 30 and 
180 beats/min do not reduce cerebral blood flow, 



especially if the person is in the supine position. As the 
heart rate decreases, ventricular filling time and stroke 
volume increase to maintain normal cardiac output. At 
rates <30 beats/min, stroke volume can no longer 
increase to compensate adequately for the decreased 
heart rate. At rates greater than ~180 beats/min, ventric- 
ular filling time is inadequate to maintain adequate 
stroke volume. In either case, cerebral hypoperfusion and 
syncope may occur. Upright posture; cerebrovascular 
disease; anemia; loss of atrioventricular synchrony; and 
coronary, myocardial, or valvular disease all reduce the 
tolerance to alterations in rate. 

Bradyarrhythmias may occur as a result of an abnor- 
mality of impulse generation (e.g., sinoatrial arrest) or 
impulse conduction (e.g., AV block). Either may cause 
syncope if the escape pacemaker rate is insufficient to 
maintain cardiac output. Syncope due to bradyarrhyth- 
mias may occur abruptly, without presyncopal symp- 
toms, and recur several times daily. Patients with sick 
sinus syndrome may have sinus pauses (>3 s), and those 
with syncope due to high-degree AV block (Stokes- 
Adams-Morgogni syndrome) may have evidence of con- 
duction system disease (e.g., prolonged PR interval, 
bundle branch block). However, the arrhythmia is often 
transitory, and the surface electrocardiogram or continu- 
ous electrocardiographic monitor (Holter monitor) taken 
later may not reveal the abnormality. The bradycardia- 
tachycardia syndrome is a common form of sinus node 
dysfunction in which syncope generally occurs as a 
result of marked sinus pauses, some following termina- 
tion of paroxysms of atrial tachyarrhythmias. Drugs 
are a common cause for bradyarrhythmias, particularly 
in patients with underlying structural heart disease. 
Digoxin, (3-adrenergic receptor antagonists, calcium chan- 
nel blockers, and many antiarrhythmic drugs may sup- 
press sinoatrial node impulse generation or slow AV nodal 
conduction. 

Syncope due to a tachyarrhythmia is usually preceded 
by palpitation or lightheadedness but may occur abruptly 
with no warning symptoms. Supraventricular tach- 
yarrhythmias are unlikely to cause syncope in individu- 
als with structurally normal hearts but may do so if 
they occur in patients with (1) heart disease that also 
compromises cardiac output, (2) cerebrovascular dis- 
ease, (3) a disorder of vascular tone or blood volume, 
or (4) a rapid ventricular rate. These tachycardias result 
most commonly from paroxysmal atrial flutter, atrial 
fibrillation, or reentry involving the AV node or acces- 
sory pathways that bypass part or all of the AV conduc- 
tion system. Patients with Wolff-Parkinson- Wliite syndrome 
may experience syncope when a very rapid ventricular 
rate occurs due to reentry across an accessory AV 
connection. 

In patients with structural heart disease, ventricular 
tachycardia is a common cause of syncope, particularly 
in those with a prior myocardial infarction. Patients with 



aortic valvular stenosis and hypertrophic obstructive car- 
diomyopathy are also at risk for ventricular tachycardia. 
Individuals with abnormalities of ventricular repolariza- 
tion (prolongation of the QT interval) are at risk to 
develop polymorphic ventricular tachycardia (torsades 
des pointes) . Those with the inherited form of this syn- 
drome often have a family history of sudden death in 
young individuals. Genetic markers can identify some 
patients with familial long-QT syndrome, but the clini- 
cal utility of these markers remains unproven. Drugs 
(i.e., certain antiarrhythmics and erythromycin) and 
electrolyte disorders (i.e., hypokalemia, hypocalcemia, 
hypomagnesemia) can prolong the QT interval and pre- 
dispose to torsades des pointes. Antiarrhythmic medica- 
tions may precipitate ventricular tachycardia, particularly 
in patients with structural heart disease. 

In addition to arrhythmias, syncope may also occur 
with a variety of structural cardiovascular disorders. 
Episodes are usually precipitated when the cardiac out- 
put cannot increase to compensate adequately for 
peripheral vasodilatation. Peripheral vasodilatation may 
be appropriate, such as following exercise, or may occur 
due to inappropriate activation of left ventricular 
mechanoreceptor reflexes, as occurs in aortic outflow 
tract obstruction (aortic valvular stenosis or hyper- 
trophic obstructive cardiomyopathy). Obstruction to 
forward flow is the most common reason that cardiac 
output cannot increase. Pericardial tamponade is a rare 
cause of syncope. Syncope occurs in up to 10% of 
patients with massive pulmonary embolism and may 
occur with exertion in patients with severe primary pul- 
monary hypertension. The cause is an inability of the 
right ventricle to provide appropriate cardiac output in 
the presence of obstruction or increased pulmonary vascu- 
lar resistance. Loss of consciousness is usually accompanied 
by other symptoms such as chest pain and dyspnea. Atrial 
myxoma, a prosthetic valve thrombus, and, rarely, mitral 
stenosis may impair left ventricular filling, decrease cardiac 
output, and cause syncope. 

CEREBROVASCULAR DISEASE 

Cerebrovascular disease alone rarely causes syncope but 
may lower the threshold for syncope in patients with 
other causes. The vertebrobasilar arteries, which supply 
brainstem structures responsible for maintaining con- 
sciousness, are usually involved when cerebrovascular 
diseases causes or contributes to syncope. An exception 
is the rare patient with tight bilateral carotid stenosis and 
recurrent syncope, often precipitated by standing or 
walking. Most patients who experience lightheadedness 
or syncope due to cerebrovascular disease also have 
symptoms of focal neurologic ischemia, such as arm or 
leg weakness, diplopia, ataxia, dysarthria, or sensory dis- 
turbances. Basilar artery migraine is a rare disorder that 
causes syncope in adolescents. 



DIFFERENTIAL DIAGNOSIS 

ANXIETY ATTACKS AND 
HYPERVENTILATION SYNDROME 

Anxiety, such as occurs in panic attacks, is frequently 
interpreted as a feeling of faintness or dizziness resem- 
bling presyncope. However, the symptoms are not 
accompanied by facial pallor and are not relieved by 
recumbency. The diagnosis is made on the basis of the 
associated symptoms such as a feeling of impending 
doom, air hunger, palpitations, and tingling of the fingers 
and perioral region. Attacks can often be reproduced 
by hyperventilation, resulting in hypocapnia, alkalosis, 
increased cerebrovascular resistance, and decreased cere- 
bral blood flow. The release of epinephrine also con- 
tributes to the symptoms. 



SEIZURES 

A seizure may be heralded by an aura, which is caused 
by a focal seizure discharge and hence has localizing 
significance (Chap. 20) . The aura is usually followed by 
a rapid return to normal or by a loss of consciousness. 
Injury from falling is frequent in a seizure and rare in 
syncope, since only in generalized seizures are protective 
reflexes abolished instantaneously. Sustained tonic-clonic 
movements are characteristic of convulsive seizures, but 
brief clonic, or tonic-clonic, seizure-like activity can 
accompany fainting episodes. The period of uncon- 
sciousness in seizures tends to be longer than in syn- 
cope. Urinary incontinence is frequent in seizures and 
rare in syncope. The return of consciousness is prompt 
in syncope and slow after a seizure. Mental confusion, 
headache, and drowsiness are common sequelae of seizures, 
whereas physical weakness with a clear sensorium char- 
acterizes the postsyncopal state. Repeated spells of uncon- 
sciousness in a young person at a rate of several per 
day or month are more suggestive of epilepsy than 
syncope. See Table 20-7 for a comparison of seizures 
and syncope. 



HYPOGLYCEMIA 

Severe hypoglycemia is usually due to a serious disease 
such as a tumor of the islets of Langerhans or advanced 
adrenal, pituitary, or hepatic disease; or to excessive 
administration of insulin. 



HYSTERICAL FAINTING 

The attack is usually unattended by an outward display 
of anxiety. Lack of change in pulse and blood pressure or 
color of the skin and mucous membranes distinguish it 
from the vasodepressor faint. 



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Approach to the Patient: 
SYNCOPE 



The diagnosis of syncope is often challenging. The 
cause may be apparent only at the time of the event, 
leaving few, if any, clues when the patient is seen later 
by the physician. The physician should think first of 
those causes that constitute a therapeutic emergency, 
including massive internal hemorrhage or myocardial 
infarction, which may be painless, and cardiac arrhyth- 
mias. In elderly persons, a sudden faint, without obvi- 
ous cause, should arouse the suspicion of complete 
heart block or a tachyarrhythmia, even though all 
findings are negative when the patient is seen. 

Figure 8-1 depicts an algorithmic approach to syn- 
cope. A careful history is the most important diagnos- 
tic tool, both to suggest the correct cause and to 
exclude important potential causes (Table 8-1). The 
nature of the events and their time course immedi- 
ately prior to, during, and after an episode of syncope 
often provide valuable etiologic clues. Loss of con- 
sciousness in particular situations, such as during 
venipuncture or micturition or with volume deple- 
tion, suggests an abnormality of vascular tone. The 
position of the patient at the time of the syncopal 
episode is important; syncope in the supine position is 
unlikely to be vasovagal and suggests an arrhythmia or 
a seizure. Syncope due to carotid sinus syndrome may 
occur when the individual is wearing a shirt -with a 
tight collar, turning the head (turning to look while 
driving in reverse), or manipulating the neck (as in 
shaving). The patient's medications must be noted, 
including nonprescription drugs or health store sup- 
plements, with particular attention to recent changes. 



Syncope 



~~ 



Normal history 
and physical 
examination 













Reflex 

syncope 












Tilt testing if 
severe or 
recurrent 



History, physical 

exam, ECG 

suggest cardiac 

disease 



Examination 

reveals 
orthostatic 
hypotension 



Review 
medication 



Echocardiogram, 
24-h Holter 

monitor, stress test, 

other cardiac 
testing as indicated 



Normal 

neurologic 

exam 



Abnormal 

neurologic 
exam 



Consider 

postganglionic 

autonomic 

insufficiency 



Peripheral 

neuropathy 

(consider diabetic, 

nutritional, 

amyloid, etc.) 



Central nervous 

sytem findings 

Consider multiple 

system atrophy 



FIGURE 8-1 

Approach to the patient with syncope. 



The physical examination should include evalua- 
tion of heart rate and blood pressure in the supine, 
sitting, and standing positions. In patients with unex- 
plained recurrent syncope, an attempt to reproduce 
an attack may assist in diagnosis. Anxiety attacks 
induced by hyperventilation can be reproduced read- 
ily by having the patient breathe rapidly and deeply 
for 2—3 min. Cough syncope may be reproduced by 
inducing the Valsalva's maneuver. Carotid sinus mas- 
sage should generally be avoided, unless carotid ultra- 
sound is negative for atheroma, because its diagnostic 
specificity is unknown and it may provoke a transient 
ischemic attack (TIA) or stroke in individuals with 
carotid atheromas. 

DIAGNOSTIC TESTS The choice of diagnostic 
tests should be guided by the history and the physical 
examination. Measurements of serum electrolytes, 
glucose, and the hematocrit are usually indicated. 
Cardiac enzymes should be evaluated if myocardial 
ischemia is suspected. Blood and urine toxicology 
screens may reveal the presence of alcohol or other 
drugs. In patients with possible adrenocortical insuffi- 
ciency, plasma aldosterone and mineralocorticoid 
levels should be obtained. 

Although the surface electrocardiogram is unlikely 
to provide a definitive diagnosis, it may provide clues 
to the cause of syncope and should be performed in 
almost all patients. The presence of conduction abnor- 
malities (PR prolongation and bundle branch block) 
suggests a bradyarrhythmia, whereas pathologic Q 
waves or prolongation of the QT interval suggests a 
ventricular tachyarrhythmia. Inpatients should undergo 
continuous electrocardiographic monitoring; outpa- 
tients should wear a Holter monitor for 24—48 h. 
Whenever possible, symptoms should be correlated 
with the occurrence of arrhythmias. Continuous elec- 
trocardiographic monitoring may establish the cause 
of syncope in as many as 15% of patients. Cardiac 
event monitors may be useful in patients with infre- 
quent symptoms, particularly in patients with presyn- 
cope. An implantable event monitor may be necessary 
for patients with extremely infrequent episodes. The 
presence of a late potential on a signal-averaged elec- 
trocardiogram is associated with increased risk for 
ventricular tachyarrhythmias in patients with a prior 
myocardial infarction. Low-voltage (visually inapparent) 
T wave alternans is also associated with development 
of sustained ventricular arrhythmias. 

Invasive cardiac electrophysiologic testing provides diag- 
nostic and prognostic information regarding sinus 
node function, AV conduction, and supraventricular 
and ventricular arrhythmias. Prolongation of the sinus 
node recovery time (>1500 ms) is a specific finding 



(85—100%) for diagnosis of sinus node dysfunction 
but has a low sensitivity; continuous electrocardio- 
graphic monitoring is usually more effective for diag- 
nosing this abnormality. Prolongation of the HV 
interval and conduction block below the His bundle 
indicate that His-Purkinje disease may be responsible 
for syncope. Programmed stimulation for ventricular 
arrhythmias is most useful in patients who have expe- 
rienced a myocardial infarction; the sensitivity and 
specificity of this technique is lower in patients with 
normal hearts or those with heart disease other than 
coronary artery disease. 

Upright tilt table testing is indicated for recurrent syn- 
cope, a single syncopal episode that caused injury or a 
single syncopal event in a "high-risk" setting (pilot, 
commercial vehicle driver, etc.), whether or not there 
is a history of preexisting heart disease or prior vaso- 
vagal episodes. In susceptible patients, upright tilt at an 
angle between 60° and 80° for 30—60 min induces a 
vasovagal episode. The protocol can be shortened if 
upright tilt is combined with administration of drugs 
that cause venous pooling or increase adrenergic stim- 
ulation (isoproterenol, nitroglycerin, edrophonium, or 
adenosine) . The sensitivity and specificity of tilt-table 
testing is difficult to ascertain because of the lack of 
validated criteria. Moreover, the reflexes responsible 
for vasovagal syncope can be elicited in most, if not 
all, individuals given the appropriate stimulus. The 
specificity of tilt-table testing has been reported to be 
near 90%, but it is lower when pharmacologic provo- 
cation is employed. The reported sensitivity of the test 
ranges between 20 and 74%, the variability due to dif- 
ferences in populations studied, techniques used, and 
the absence of a true "gold standard" against which to 
compare test results. The reproducibility (in a time 
ranging from several hours to weeks) is 80—90% for an 
initially positive response, but may be less for an ini- 
tially negative response (ranging from 30 to 90%). 

A variety of other tests may be useful to determine 
the presence of structural heart disease that may cause 
syncope. The echocardiogram with Doppler examina- 
tion detects valvular, myocardial, and pericardial abnor- 
malities. The echocardiogram is the "gold standard" for 
the diagnosis of hypertrophic cardiomyopathy and 
atrial myxoma. Cardiac cine MRI provides an alterna- 
tive noninvasive modality that may be useful for 
patients in whom diagnostic-quality echocardiographic 
images cannot be obtained. This test is also indicated 
for patients suspected of having arrhythmogenic right 
ventricular dysplasia or right ventricular outflow tract 
ventricular tachycardia. Both are associated with right 
ventricular structural abnormalities that are better visu- 
alized on MR imaging than by echocardiogram. Exer- 
cise testing may detect ischemia or exercise-induced 



arrhythmias. In some patients, cardiac catheterization 
may be necessary to diagnose the presence or severity 
of coronary artery disease or valvular abnormalities. 
Ultrafast CT scan, ventilation-perfusion scan, or pul- 
monary angiography is indicated in patients in whom 
syncope may be due to pulmonary embolus. 

In cases of possible cerebrovascular syncope, neu- 
roimaging tests may be indicated, including Doppler 
ultrasound studies of the carotid and vertebrobasilar 
systems, MRI, magnetic resonance angiography, and 
x-ray angiography of the cerebral vasculature (Chap. 2). 
Electroencephalography is indicated if seizures are 
suspected. 



93 



Be 



Treatment: 
SYNCOPE 



The treatment of syncope is directed at the underlying 
cause. This discussion will focus on disorders of auto- 
nomic control. Cerebrovascular disorders are discussed 
in Chap. 21. 

Certain precautions should be taken regardless of 
the cause of syncope. At the first sign of symptoms, 
patients should make every effort to avoid injury should 
they lose consciousness. Patients with frequent 
episodes, or those who have experienced syncope with- 
out warning symptoms, should avoid situations in 
which sudden loss of consciousness might result in 
injury (e.g., climbing ladders, swimming alone, operat- 
ing heavy machinery, driving). Patients should lower 
their head to the extent possible and preferably should 
lie down. Lowering the head by bending at the waist 
should be avoided because it may further compromise 
venous return to the heart. When appropriate, family 
members or other close contacts should be educated as 
to the problem. This will ensure appropriate therapy 
and may prevent delivery of inappropriate therapy 
(chest compressions associated with cardiopulmonary 
resuscitation) that may inflict trauma. 

Patients who have lost consciousness should be 
placed in a position that maximizes cerebral blood flow, 
offers protection from trauma, and secures the airway. 
Whenever possible, the patient should be placed supine 
with the head turned to the side to prevent aspiration 
and the tongue from blocking the airway. Assessment 
of the pulse and direct cardiac auscultation may assist 
in determining if the episode is associated with a brad- 
yarrhythmia or a tachyarrhythmia. Clothing that fits 
tightly around the neck or waist should be loosened. 
Peripheral stimulation, such as sprinkling cold water on 
the face, may be helpful. Patients should not be given 



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anything by mouth or be permitted to rise until the 
sense of physical weakness has passed. 

Patients with vasovagal syncope should be instructed 
to avoid situations or stimuli that have caused them to 
lose consciousness and to assume a recumbent position 
when premonitory symptoms occur. These behavioral 
modifications alone may be sufficient for patients with 
infrequent and relatively benign episodes of vasovagal 
syncope, particularly when loss of consciousness occurs 
in response to a specific stimulus. Tilt training (standing 
and leaning against a wall for progressively longer peri- 
ods each day) has been used with limited success, par- 
ticularly for patients with orthostatic intolerance. 
Episodes associated with intravascular volume deple- 
tion may be prevented by salt and fluid loading prior to 
provocative events. 

Drug therapy may be necessary when vasovagal syn- 
cope is resistant to the above measures, when episodes 
occur frequently, or when syncope is associated with a 
significant risk for injury. (3-Adrenergic receptor antago- 
nists (metoprolol, 25-50 mg bid; atenolol, 25-50 mg qd; 
or nadolol, 10-20 mg bid; all starting doses), the most 
widely used agents, mitigate the increase in myocardial 
contractility that stimulates left ventricular mechanore- 
ceptors and also block central serotonin receptors. Sero- 
tonin reuptake inhibitors (paroxetine, 20-40 mg qd; or 
sertraline, 25-50 mg qd), appear to be effective for 
some patients. Bupropion SR (1 50 mg qd), another anti- 
depressant, has also been used with success. (3-Adrener- 
gic receptor antagonists and serotonin reuptake 
inhibitors are well tolerated and are often used as first- 
line agents for younger patients. Hydrofludrocortisone 
(0.1-0.2 mg qd), a mineralocorticoid, promotes sodium 
retention, volume expansion, and peripheral vasocon- 
striction by increasing (3-receptor sensitivity to endoge- 
nous catecholamines. Hydrofludrocortisone is useful for 
patients with intravascular volume depletion and for 
those who also have postural hypotension. Proamatine 
(2.5-1 mg bid or tid), an a-agonist, has been used as a 
first-line agent for some patients. In a randomized con- 
trolled trial, proamatine was more effective than 
placebo in preventing syncope during an upright tilt- 
test. However, in some patients, proamatine and 
hydrofludrocortisone may increase resting supine sys- 
temic blood pressure, which may be problematic for 
those with hypertension. 

Disopyramide (150 mg bid), a vagolytic antiarrhyth- 
mic drug with negative inotropic properties, and trans- 
dermal scopolamine, another vagolytic, have been used 
to treat vasovagal syncope, as have theophylline and 
ephedrine. Side effects associated with these drugs 
have limited their use for this indication. Disopyramide 
is a type 1A antiarrhythmic drug and should be used 
with great caution, if at all, in patients who are at risk for 
ventricular arrhythmias. 



Although several clinical trials have suggested that 
pharmacologic therapy for neurocardiogenic syncope is 
effective, the few long-term prospective randomized 
controlled trials have yielded mixed results. In the Pre- 
vention of Syncope Trial (POST), metoprolol was ineffec- 
tive in patients <42 years but decreased the incidence 
of syncope in patients >42 years, raising the possibility 
that there may be significant age-related differences in 
response to pharmacologic therapy. 

Studies of permanent pacing for neurocardiogenic 
syncope have also yielded mixed results. Dual-chamber 
cardiac pacing may be effective for patients with fre- 
quent episodes of vasovagal syncope, particularly for 
those with prolonged asystole associated with vasova- 
gal episodes. Pacemakers that can be programmed to 
transiently pace at a high rate (90-100 beats/min) after 
a profound drop in the patient's intrinsic heart rate are 
most effective. 

Patients with orthostatic hypotension should be 
instructed to rise slowly and systematically (supine to 
seated, seated to standing) from the bed or a chair. 
Movement of the legs prior to rising facilitates venous 
return from the lower extremities. Whenever possible, 
medications that aggravate the problem (vasodilators, 
diuretics, etc.) should be discontinued. Elevation of the 
head of the bed [20-30 cm (8-12 in.)] and use of com- 
pression stockings may help. 

Additional therapeutic modalities include salt load- 
ing and a variety of pharmacologic agents including 
sympathomimetic amines, monamine oxidase inhibitors, 
beta blockers, and levodopa.The treatment of orthosta- 
tic hypotension secondary to central or peripheral 
disorders of the autonomic nervous system is discussed 
in Chap. 28. 

Glossopharyngeal neuralgia is treated with carba- 
mazepine, which is effective for syncope as well as for 
pain. Patients with carotid sinus hypersensitivity should 
be instructed to avoid clothing and situations that 
stimulate carotid sinus baroreceptors.They should turn 
their entire body, rather than just their head, when look- 
ing to the side. Those with intractable syncope due 
to the cardioinhibitory response to carotid sinus 
stimulation should undergo permanent pacemaker 
implantation. 

Patients with syncope should be hospitalized when 
there is a possibility that the episode may have resulted 
from a life-threatening abnormality or if recurrence with 
significant injury seems likely. These individuals should 
be admitted to a bed with continuous electrocardio- 
graphic monitoring. Patients who are known to have a 
normal heart and for whom the history strongly sug- 
gests vasovagal or situational syncope may be treated 
as outpatients if the episodes are neither frequent nor 
severe. 



FURTHER READINGS 

BEND1TT DG, NGUYEN JT: Syncope: Therapeutic approaches. J Am Coll 

Cardiol. 53:1741,2009 
GRUBB BP: Neurocardiogenic syncope and related disorders of 

orthostatic intolerance. Circulation 111:2997,2005 
, OLSHANSKY B (eds): Syncope: Mechanisms and Management, 

2d ed. Maiden, Mass., Blackwell Futura, 2005 
KAPOOR WN: Current evaluation in management of syncope. Circu- 
lation 106:1606,2002 
Kerr SRJ et al: Carotid sinus hypersensitivity in asymptomatic older 

persons: Implications for diagnosis of syncope and falls. Arch 

Intern Med 166:515,2006 
MaiselW, STEBENSONW: Syncope — getting to the heart of the matter. 

N Engl J Med 347:931, 2002 



NORCLIFFE-KAUFMANN LJ et al: Enhanced vascular responses to 
hypocapnia in neurally mediated syncope. Ann Neurol 63:288, 2008 

SOTERIADES E et al: Incidence and prognosis of syncope. N Engl J 
Med 347:878, 2002 

STRICKBERGER SA et al: AHA/ACCF scientific statement on the 
evaluation of syncope: From the American Heart Association 
Councils on Clinical Cardiology, Cardiovascular Nursing, Car- 
diovascular Disease in the Young, and Stroke, and the Quality of 
Care and Outcomes Research Interdisciplinary Working Group; 
and the American College of Cardiology Foundation: In collab- 
oration with the Heart Rhythm Society: Endorsed by the Amer- 
ican Autonomic Society. Circulation 113(2):316, 2006 

VAN DlJK N et al: Quality of life within one year following presenta- 
tion after transient loss of consciousness. Am J Cardiol 100:672, 
2007 



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Robert B. Daroff 



Faintness 96 

Vertigo 96 

Miscellaneous Head Sensations 99 

Global Considerations 1 01 

Further Readings 1 01 



Dizziness is a common and often vexing symptom. 
Patients use the term to encompass a variety of sensa- 
tions, including those that seem semantically appropriate 
(e.g., lightheadedness, faintness, spinning, giddiness) and 
those that are misleadingly inappropriate, such as mental 
confusion, blurred vision, headache, or tingling. More- 
over, some individuals with gait disorders caused by 
peripheral neuropathy, myelopathy, spasticity, parkinson- 
ism, or cerebellar ataxia have complaint of "dizziness" 
despite the absence of vertigo or other abnormal 
cephalic sensations. In this context, the term dizziness is 
being used to describe disturbed ambulation. There may 
be mild associated lightheadedness, particularly with 
impaired sensation from the feet or poor vision; this is 
known as multiple-sensory-defect dizziness and occurs in 
elderly individuals who complain of dizziness only 
when walking. Decreased position sense (secondary to 
neuropathy or myelopathy) and poor vision (from 
cataracts or retinal degeneration) create an overreliance 
on the aging vestibular apparatus. A less precise but 
sometimes comforting designation to patients is benign 
dysequilibrium of aging. Thus, a careful history is necessary 
to determine exactly what a patient who states, "Doctor, 
I'm dizzy," is experiencing. After eliminating the mis- 
leading symptoms or gait disturbance, "dizziness" usually 
means either faintness (presyncope) or vertigo (an illusory 
or hallucinatory sense of movement of the body or 
environment, most often a feeling of spinning). Opera- 
tionally, after obtaining the history, dizziness may be 
classified into three categories: (1) faintness, (2) vertigo, 
and (3) miscellaneous head sensations. 



96 



FAINTNESS 

Prior to an actual faint (syncope), there are often pro- 
dromal presyncopal symptoms (faintness) reflecting 
ischemia to a degree insufficient to impair conscious- 
ness. These include lightheadedness, "dizziness" without 
true vertigo, a feeling of warmth, diaphoresis, nausea, 
and visual blurring occasionally proceeding to blindness. 
Presyncopal symptoms vary in duration and may 
increase in severity until loss of consciousness occurs or 
may resolve prior to loss of consciousness if the cerebral 
ischemia is corrected. Faintness and syncope are dis- 
cussed in detail in Chap. 8. 



VERTIGO 

Vertigo is usually due to a disturbance in the vestibular 
system. The end organs of this system, situated in the 
bony labyrinths of the inner ears, consist of the three 
semicircular canals and the otolithic apparatus (utricle 
and saccule) on each side. The canals transduce angular 
acceleration, while the otoliths transduce linear accelera- 
tion and the static gravitational forces that provide a 
sense of head position in space. The neural output of the 
end organs is conveyed to the vestibular nuclei in the 
brainstem via the eighth cranial nerves. The principal 
projections from the vestibular nuclei are to the nuclei of 
cranial nerves III, IV, and VI; spinal cord; cerebral cortex; 
and cerebellum. The vestibulo ocular reflex (VOR) serves 
to maintain visual stability during head movement and 
depends on direct projections from the vestibular nuclei 



to the sixth cranial nerve (abducens) nuclei in the pons 
and, via the medial longitudinal fasciculus, to the third 
(oculomotor) and fourth (trochlear) cranial nerve nuclei 
in the midbrain. These connections account for the nys- 
tagmus (to-and-fro oscillation of the eyes) that is an almost 
invariable accompaniment of vestibular dysfunction. The 
vestibular nerves and nuclei project to areas of the cerebel- 
lum (primarily the flocculus and nodulus) that modulate 
the VOR. The vestibulospinal pathways assist in the 
maintenance of postural stability. Projections to the cere- 
bral cortex, via the thalamus, provide conscious awareness 
of head position and movement. 

The vestibular system is one of three sensory systems 
subserving spatial orientation and posture; the other two 
are the visual system (retina to occipital cortex) and the 
somatosensory system that conveys peripheral informa- 
tion from skin, joint, and muscle receptors. The three sta- 
bilizing systems overlap sufficiently to compensate (partially 
or completely) for each other's deficiencies. Vertigo may 
represent either physiologic stimulation or pathologic 
dysfunction in any of the three sensory systems. 



Physiologic Vertigo 

This occurs in normal individuals when (1) the brain is 
confronted with an intersensory mismatch among the 
three stabilizing sensory systems; (2) the vestibular sys- 
tem is subjected to unfamiliar head movements to 
which it is unadapted, such as in seasickness; (3) unusual 
head/neck positions, such as the extreme extension 
when painting a ceiling; or (4) following a spin. Inter- 
sensory mismatch explains carsickness, height vertigo, 
and the visual vertigo most commonly experienced dur- 
ing motion picture chase scenes; in the latter, the visual 
sensation of environmental movement is unaccompa- 
nied by concomitant vestibular and somatosensory 
movement cues. Space sickness, a frequent transient effect 
of active head movement in the weightless zero-gravity 
environment, is another example of physiologic vertigo. 



Pathologic Vertigo 

This results from lesions of the visual, somatosensory, or 
vestibular systems. Visual vertigo is caused by new or 
incorrect eyeglasses or by the sudden onset of an 
extraocular muscle paresis with diplopia; in either 
instance, central nervous system (CNS) compensation 
rapidly counteracts the vertigo. Somatosensory vertigo, 
rare in isolation, is usually due to a peripheral neuropa- 
thy or myelopathy that reduces the sensory input neces- 
sary for central compensation when there is dysfunction 
of the vestibular or visual systems. 

The most common cause of pathologic vertigo is 
vestibular dysfunction involving either its end organ 
(labyrinth), nerve, or central connections. The vertigo is 



CD 



O 



associated with jerk nystagmus and is frequently accom- 97 
panied by nausea, postural unsteadiness, and gait ataxia. 
Since vertigo increases with rapid head movements, 
patients tend to hold their heads still. 



^H Labyrinthine Dysfunction 

This causes severe rotational or linear vertigo. When rota- 
tional, the hallucination of movement, whether of envi- 
ronment or self, is directed away from the side of the 
lesion. The fast phases of nystagmus beat away from the 
lesion side, and the tendency to fall is toward the side of 
the lesion, particularly in darkness or with the eyes closed. 

Under normal circumstances, when the head is straight 
and immobile, the vestibular end organs generate a tonic 
resting firing frequency that is equal from the two sides. 
With any rotational acceleration, the anatomic positions 
of the semicircular canals on each side necessitate an 
increased firing rate from one and a commensurate 
decrease from the other. This change in neural activity is 
ultimately projected to the cerebral cortex, where it is 
summed with inputs from the visual and somatosensory 
systems to produce the appropriate conscious sense of 
rotational movement. After cessation of prolonged rota- 
tion, the firing frequencies of the two end organs 
reverse; the side with the initially increased rate decreases, 
and the other side increases. A sense of rotation in the 
opposite direction is experienced; since there is no 
actual head movement, this hallucinatory sensation is 
physiologic postrotational vertigo. 

Any disease state that changes the firing frequency of 
an end organ, producing unequal neural input to the 
brainstem and ultimately the cerebral cortex, causes ver- 
tigo. The symptom can be conceptualized as the cortex 
inappropriately interpreting the abnormal neural input 
as indicating actual head rotation. Transient abnormali- 
ties produce short-lived symptoms. With a fixed unilat- 
eral deficit, central compensatory mechanisms ultimately 
diminish the vertigo. Since compensation depends on 
the plasticity of connections between the vestibular 
nuclei and the cerebellum, patients with brainstem or 
cerebellar disease have diminished adaptive capacity, and 
symptoms may persist indefinitely. Compensation is 
always inadequate for severe fixed bilateral lesions 
despite normal cerebellar connections; these patients are 
permanently symptomatic when they move their heads. 

Acute unilateral labyrinthine dysfunction is caused by 
infection, trauma, and ischemia. Often, no specific etiol- 
ogy is uncovered, and the nonspecific terms acute 
labyrinthitis, acute peripheral vestibulopathy, or vestibular neu- 
ritis are used to describe the event. The vertiginous 
attacks are brief and leave the patient with mild vertigo 
for several days. Infection with herpes simplex virus type 
1 has been implicated. It is impossible to predict 
whether a patient recovering from the first bout of ver- 
tigo will have recurrent episodes. 



o 



a> 



98 Labyrinthine ischemia, presumably due to occlusion 
of the labyrinthine branch of the internal auditory 
artery may be the sole manifestation of vertebrobasilar 
insufficiency (Chap. 21); patients with this syndrome 
present with the abrupt onset of severe vertigo, nausea, 
and vomiting, but without tinnitus or hearing loss. 

Acute bilateral labyrinthine dysfunction is usually the 
result of toxins such as drugs or alcohol. The most com- 
mon offending drugs are the aminoglycoside antibiotics 
that damage the hair cells of the vestibular end organs 
and may cause a permanent disorder of equilibrium. 

Recurrent unilateral labyrinthine dysfunction, in associa- 
tion with signs and symptoms of cochlear disease (pro- 
gressive hearing loss and tinnitus), is usually due to 
Meniere's disease (Chap. 18). When auditory manifesta- 
tions are absent, the term vestibular neuronitis denotes 
recurrent monosymptomatic vertigo. Transient ischemic 
attacks of the posterior cerebral circulation (verte- 
brobasilar insufficiency) only infrequently cause recur- 
rent vertigo without concomitant motor, sensory, visual, 
cranial nerve, or cerebellar signs (Chap. 21). 

Positional vertigo is precipitated by a recumbent head 
position, either to the right or to the left. Benign parox- 
ysmal positional (or positioning) vertigo (BPPV) of the 
posterior semicircular canal is particularly common. 
Although the condition may be due to head trauma, 
usually no precipitating factors are identified. It generally 
abates spontaneously after weeks or months. The vertigo 
and accompanying nystagmus have a distinct pattern of 
latency, fatigability, and habituation that differs from the 
less common central positional vertigo (Table 9-1) due 
to lesions in and around the fourth ventricle. Moreover, 
the pattern of nystagmus in posterior canal BPPV is dis- 
tinctive. When supine, with the head turned to the side 
of the offending ear (bad ear down), the lower eye dis- 
plays a large-amplitude torsional nystagmus, and the upper 
eye has a lesser degree of torsion combined with upbeat- 
ing nystagmus. If the eyes are directed to the upper ear, 



TABLE 9-1 



BENIGN PAROXYSMAL POSITIONAL VERTIGO AND 
CENTRAL POSITIONAL VERTIGO 



a> 
ST 
o' 



FEATURES 


BPPV 


CENTRAL 


Latency 3 


3^10 s 


None: immediate 
vertigo and nystagmus 


Fatigability" 


Yes 


No 


Habituation 


Yes 


No 


Intensity of vertigo 


Severe 


Mild 


Reproducibility ' 


Variable 


Good 



Time between attaining head position and onset of symptoms. 
^Disappearance of symptoms with maintenance of offending posi- 
tion. 

lessening of symptoms with repeated trials. 
d Likelihood of symptom production during any examination session. 



the vertical nystagmus in the upper eye increases in 
amplitude. Mild dysequilibrium when upright may also 
be present. 

A perilymphatic fistula should be suspected when 
episodic vertigo is precipitated by Valsalva or exertion, 
particularly upon a background of a stepwise progressive 
sensory-neural hearing loss. The condition is usually 
caused by head trauma or barotrauma or occurs after 
middle ear surgery. 

^H Vertigo of Vestibular Nerve Origin 

This occurs with diseases that involve the nerve in the 
petrous bone or the cerebellopontine angle. Although 
less severe and less frequently paroxysmal, it has many of 
the characteristics of labyrinthine vertigo. The adjacent 
auditory division of the eighth cranial nerve is usually 
affected, which explains the frequent association of ver- 
tigo with unilateral tinnitus and hearing loss. The most 
common cause of eighth cranial nerve dysfunction is a 
tumor, usually a schwannoma (acoustic neuroma) or a 
meningioma. These tumors grow slowly and produce 
such a gradual reduction of labyrinthine output that 
central compensatory mechanisms can prevent or mini- 
mize the vertigo; auditory symptoms are the most com- 
mon manifestations. 

^H Central Vertigo 

Lesions of the brainstem or cerebellum can cause acute 
vertigo, but associated signs and symptoms usually permit 
distinction from a labyrinthine etiology (Table 9-2). 
Occasionally, an acute lesion of the vestibulocerebellum 
may present with monosymptomatic vertigo indistin- 
guishable from a labyrinthopathy 

Vertigo may be a manifestation of a migraine aura 
(Chap. 6), but some patients with migraine have 
episodes of vertigo unassociated with their headaches. 
Antimigrainous treatment should be considered in such 
patients with otherwise enigmatic vertiginous episodes. 

Vestibular epilepsy, vertigo secondary to temporal lobe 
epileptic activity, is rare and almost always intermixed 
with other epileptic manifestations. 

^H Psychogenic Vertigo 

This is sometimes called phobic postural vertigo and is 
usually a concomitant of panic attacks (Chap. 49) or 
agoraphobia (fear of large open spaces, crowds, or leav- 
ing the safety of home). It should be suspected in 
patients so "incapacitated" by their symptoms that they 
adopt a prolonged housebound status. Most patients 
with organic vertigo attempt to function despite their 
discomfort. Organic vertigo is accompanied by nystag- 
mus; a psychogenic etiology is almost certain when nys- 
tagmus is absent during a vertiginous episode. The 
symptoms often develop after an episode of acute 
labyrinthine dysfunction. 



TABLE 9-2 



FEATURES OF PERIPHERAL AND CENTRAL VERTIGO 



99 



SIGN OR SYMPTOM 



PERIPHERAL (LABYRINTH) 



CENTRAL (BRAINSTEM 
OR CEREBELLUM) 



Direction of associated nystagmus 


Unidirectional; fast phase opposite lesion 3 


Bidirectional or unidirectional 


Purely horizontal nystagmus without 


Uncommon 


Common 


torsional component 






Vertical or purely torsional 


Never present 


May be present 


nystagmus 






Visual fixation 


Inhibits nystagmus and vertigo 


No inhibition 


Severity of vertigo 


Marked 


Often mild 


Direction of spin 


Toward fast phase 


Variable 


Direction of fall 


Toward slow phase 


Variable 


Duration of symptoms 


Finite (minutes, days, weeks) but recurrent 


May be chronic 


Tinnitus and/or 


Often present 


Usually absent 


deafness 






Associated CNS 


None 


Extremely common (e.g., diplopia, 


abnormalities 




hiccups, cranial neuropathies, 
dysarthria) 


Common causes 


BPPV, infection (labyrinthitis), Meniere's, 


Vascular, demyelinating, 




neuronitis, ischemia, trauma, toxin 


neoplasm 



a ln Meniere's disease, the direction of the fast phase is variable. 



CD 

■=> 

< 
CO 

o 



MISCELLANEOUS HEAD SENSATIONS 

This designation is used, primarily for purposes of initial 
classification, to describe dizziness that is neither faint- 
ness nor vertigo. Cephalic ischemia or vestibular dys- 
function may be of such low intensity that the usual 
symptomatology is not clearly identified. For example, a 
small decrease in blood pressure or a slight vestibular 
imbalance may cause sensations different from distinct 
faintness or vertigo but that may be identified properly 
by provocative testing techniques (see below). Other 
causes of dizziness in this category are hyperventilation 
syndrome, hypoglycemia, and the somatic symptoms of a 
clinical depression; these patients should all have normal 
neurologic examinations and vestibular function tests. 
Depressed patients often insist that the depression is 
"secondary" to the dizziness. 



Approach to the Patient: 

DIZZINESS AND VERTIGO 

The most important diagnostic tool is a detailed history 
focused on the meaning of "dizziness" to the patient. Is 
it faintness (presyncope)? Is there a sensation of spin- 
ning? If either of these is affirmed and the neurologic 
examination is normal, appropriate investigations for 
the multiple causes of cephalic ischemia, presyncope 
(Chap. 8), or vestibular dysfunction are undertaken. 

When the meaning of "dizziness" is uncertain, 
provocative tests may be helpful. These office procedures 



simulate either cephalic ischemia or vestibular dys- 
function. Cephalic ischemia is obvious if the dizziness 
is duplicated during maneuvers that produce ortho- 
static hypotension. Further provocation involves the 
Valsalva maneuver, which decreases cerebral blood 
flow and should reproduce ischemic symptoms. 

Hyperventilation is the cause of dizziness in many 
anxious individuals; tingling of the hands and face 
may be absent. Forced hyperventilation for 1 min is 
indicated for patients with enigmatic dizziness and 
normal neurologic examinations. 

The simplest provocative test for vestibular dys- 
function is rapid rotation and abrupt cessation of 
movement in a swivel chair. This always induces ver- 
tigo that the patients can compare with their sympto- 
matic dizziness. The intense induced vertigo may be 
unlike the spontaneous symptoms, but shortly there- 
after, when the vertigo has all but subsided, a light- 
headedness supervenes that may be identified as "my 
dizziness." When this occurs, the dizzy patient, origi- 
nally classified as suffering from "miscellaneous head 
sensations," is now properly diagnosed as having mild 
vertigo secondary to a vestibulopathy. 

Patients with symptoms of positional vertigo should 
be appropriately tested (Table 9-1). A final provoca- 
tive and diagnostic vestibular test, requiring the use of 
Frenzel eyeglasses (self-illuminated goggles with con- 
vex lenses that blur out the patient's vision, but allow 
the examiner to see the eyes greatly magnified), is 
vigorous head shaking in the horizontal plane for 



100 



a> 

5T 

o' 



o 
in 



a> 



about 10 s. If nystagmus develops after the shaking 
stops, even in the absence of vertigo, vestibular dys- 
function is demonstrated. The maneuver can then be 
repeated in the vertical plane. If the provocative tests 
establish the dizziness as a vestibular symptom, an 
evaluation of vestibular vertigo is undertaken. 

EVALUATION OF PATIENTS WITH PATHO- 
LOGIC VESTIBULAR VERTIGO The evaluation 
depends on whether a central etiology is suspected 
(Table 9-2). If so, MRI of the head is mandatory. Such 
an examination is rarely helpful in cases of recurrent 
monosymptomatic vertigo with a normal neurologic 
examination. Typical BPPV requires no investigation 
after the diagnosis is made (Table 9-1). 

Vestibular function tests serve to (1) demonstrate an 
abnormality when the distinction between organic 
and psychogenic is uncertain, (2) establish the side of 
the abnormality, and (3) distinguish between peripheral 
and central etiologies. The standard test is electronys- 
tagmography (calorics), where warm and cold -water 
(or air) are applied, in a prescribed fashion, to the 
tympanic membranes, and the slow-phase velocities 
of the resultant nystagmus from the two are com- 
pared. A velocity decrease from one side indicates 
hypofunction ("canal paresis"). An inability to induce 
nystagmus with ice water denotes a "dead labyrinth." 
Some institutions have the capability of quantitatively 
determining various aspects of the VOR using com- 
puter-driven rotational chairs and precise oculo- 
graphy recording of the eye movements. 

CNS disease can produce dizzy sensations of all 
types. Consequently, a neurologic examination is always 
required even if the history or provocative tests suggest 
a cardiac, peripheral vestibular, or psychogenic etiology. 
Any abnormality on the neurologic examination 
should prompt appropriate neurodiagnostic studies. 



TABLE 9-3 



TREATMENT OF VERTIGO 



AGENT 3 


DOSE 6 


Antihistamines 




Meclizine 


25-50 mg 3 times/day 


Dimenhydrinate 


50 mg 1-2 times/day 


Promethazine 


25-50-mg suppository 




orIM 


Benzodiazepines 




Diazepam 


2.5 mg 1-3 times/day 


Clonazepam 


0.25 mg 1-3 times/day 


Phenothiazines 




Prochlorperazine 


5 mg IM or 25 mg 




suppository 


Anticholinergic " 




Scopolamine transdermal 


Patch 


Sympathomimetics 01 




Ephedrine 


25 mg/d 


Combination preparations 0. 




Ephedrine and promethazine 


25 mg/d of each 


Exercise therapy 




Repositioning maneuvers 6 




Vestibular rehabilitation' 




Other 




Diuretics or low-salt (1 g/d) diet 9 




Antimigrainous drugs" 




Inner ear surgery' 




Prednisone 


100 mg/d for 3 days, 




tapered by 20 mg 




every 3 days 



a AII listed drugs are U.S. Food and Drug Administration approved, 
but most are not approved for the treatment of vertigo. 
fa Usual oral (unless otherwise stated) starting dose in adults; mainte- 
nance dose can be reached by a gradual increase. 
c For acute vertigo only. 
d For motion sickness only. 
e For benign paroxysmal positional vertigo. 
'For vertigo other than Meniere's and positional. 
9 For Meniere's disease. 

''For migraine-associated vertigo (see Chap. 6 for a listing of prophy- 
lactic antimigrainous drugs). 
'For perilymphatic fistula and refractory cases of Meniere's disease. 



"k 



Treatment: 
VERTIGO 



Treatment of acute vertigo consists of bed rest (1-2 days 
maximum) and vestibular suppressant drugs such as 
antihistaminics (meclizine, dimenhydrinate, promet- 
hazine), tranquilizers with GABA-ergic effects (diazepam, 
clonazepam), phenothiazines (prochlorperazine), or glu- 
cocorticoids (Table 9-3). If the vertigo persists beyond a 
few days, most authorities advise ambulation in an 
attempt to induce central compensatory mechanisms, 
despite the short-term discomfort to the patient. 
Chronic vertigo of labyrinthine origin may be treated 
with a systematized vestibular rehabilitation program to 
facilitate central compensation. 



Posterior semicircular canal BPPV, the most common 
type, is often self-limited but, when persistent, may 
respond dramatically to specific repositioning exercise 
programs designed to empty particulate debris from 
the canal. One of these exercises, the Epley procedure, is 
graphically demonstrated, in four languages, on a website 
for use in both physicians' offices and self-treatment: 
www.charite.de/ch/neuro/vertigo.html 

Prophylactic measures to prevent recurrent vertigo 
are variably effective. Antihistamines are commonly uti- 
lized but are of limited value. Meniere's disease may 
respond to a diuretic or, more effectively, to a very low 
salt diet (1 g/d). Recurrent episodes of migraine-associ- 
ated vertigo should be treated with antimigrainous 



therapy (Chap. 6). There are a variety of inner ear surgi- 
cal procedures for refractory Meniere's disease, but 
these are only rarely necessary. 

Psychogenic ("phobic postural") vertigo is best 
treated with cognitive-behavioral therapy. 

Helpful websites for both physicians and vertigo 
patients: www.iVertigo.net and www.tchain.com. 



GLOBAL CONSIDERATIONS 

/^^ There are no epidemiologic studies indicating an 
B increased frequency of specific types of vertigo 
in different geographical areas. However, whereas 
BPPV of the posterior semicircular canal is overwhelm- 
ingly the most common form of positional vertigo in 
most countries, there seems to be an unusually large 



number of reports of horizontal (lateral) BPPV from 101 
Italy and Korea. 

FURTHER READINGS 

FIFE TD et al: Practice parameter: Therapies for benign paroxysmal 
positional vertigo (an evidence-based review). Neurology 
70:2067, 2008 

HALMAGI GM: Diagnosis and management of vertigo. Clin Med 
5:159,2005 

Leigh RJ, Zee DS: Neurology of Eye Movement, 4th ed. New York, 
Oxford, 2006, 76-79; 559-597 

SAJJADI H, PAPARELLA MM: Meniere's disease. Lancet 372:406, 2008 

STRUPP M et al: Methylprednisolone, valacyclovir, or the combina- 
tion for vestibular neuritis. N Engl J Med 351:354, 2004 

, BRANDT T: Pharmacological advances in the treatment of 

neuro-otological and eye movement disorders. Curr Opin Neu- 
rol 19:33, 2006 2 

ZlNGLER VC et al: Causative factors and epidemiology of bilateral !ii. 
vestibulopathy in 255 patients. Ann Neurol 61:524, 2007 rD 

on 
CD 

< 
CD 



O 




Michael J. Aminoff 



Normal motor function involves integrated muscle 
activity that is modulated by the activity of the cerebral 
cortex, basal ganglia, cerebellum, and spinal cord. Motor 
system dysfunction leads to weakness or paralysis, which 
is discussed in this chapter, or to ataxia (Chap. 26) or 
abnormal movements (Chaps. 24 and 25). The mode of 
onset, distribution, and accompaniments of weakness 
help to suggest its cause. 

Weakness is a reduction in the power that can be 
exerted by one or more muscles. Increased fatigability 
or limitation in function due to pain or articular stiff- 
ness is often confused with weakness by patients. 
Increased fatigability is the inability to sustain the perfor- 
mance of an activity that should be normal for a person 
of the same age, gender, and size. Increased time is 
sometimes required for full power to be exerted, and 
this bradykinesia may be misinterpreted as weakness. 
Severe proprioceptive sensory loss may also lead to 
complaints of weakness because adequate feedback 
information about the direction and power of move- 
ments is lacking. Finally, apraxia, a disorder of planning 
and initiating a skilled or learned movement unrelated 
to a significant motor or sensory deficit (Chap. 15), is 
sometimes mistaken for weakness by inexperienced 
medical staff. 

Paralysis indicates weakness that is so severe that the 
muscle cannot be contracted at all, whereas paresis refers 
to weakness that is mild or moderate. The prefix "hemi- 
" refers to one half of the body, "para-" to both legs, and 
"quadri-" to all four limbs. The suffix "-plegia" signifies 
severe weakness or paralysis. 

Weakness or paralysis is typically accompanied by 
other neurologic abnormalities that help to indicate the 
site of the responsible lesion. These include changes in 
tone, muscle bulk, muscle stretch reflexes, and cutaneous 
reflexes (Table 10-1). 

Tone is the resistance of a muscle to passive stretch. 
Central nervous system (CNS) abnormalities that cause 



weakness generally produce spasticity, an increase in tone 
associated with disease of upper motor neurons. Spastic- 
ity is velocity-dependent, has a sudden release after 
reaching a maximum (the "clasp-knife" phenomenon), 
and predominantly affects the antigravity muscles (i.e., 
upper-limb flexors and lower-limb extensors). Spasticity 
is distinct from rigidity and paratonia, two other types of 
hypertonia. Rigidity is increased tone that is present 
throughout the range of motion (a "lead pipe" or "plas- 
tic" stiffness) and affects flexors and extensors equally; it 
sometimes has a cogwheel quality that is enhanced by 
voluntary movement of the contralateral limb (rein- 
forcement). Rigidity occurs with certain extrapyramidal 
disorders such as Parkinson's disease. Paratonia (or gegen- 
halten) is increased tone that varies irregularly in a man- 
ner that may seem related to the degree of relaxation, is 
present throughout the range of motion, and affects 
flexors and extensors equally; it usually results from dis- 
ease of the frontal lobes. Weakness with decreased tone 
(flaccidity) or normal tone occurs with disorders of motor 
units. A motor unit consists of a single lower motor neu- 
ron and all of the muscle fibers that it innervates. 

Muscle bulk is generally unaffected in patients with 
upper motor neuron lesions, although mild disuse atro- 
phy may eventually occur. By contrast, atrophy is often 
conspicuous when a lower motor neuron lesion is 
responsible for weakness and may also occur with 
advanced muscle disease. 

Muscle stretch (tendon) reflexes are usually increased 
with upper motor neuron lesions, although they may be 
decreased or absent for a variable period immediately 
after onset of an acute lesion. This is usually — but not 
invariably — accompanied by abnormalities of cutaneous 
reflexes (such as superficial abdominals; Chap. 1) and, in 
particular, by an extensor plantar (Babinski) response. 
The muscle stretch reflexes are depressed in patients 
with lower motor neuron lesions when there is direct 
involvement of specific reflex arcs. The stretch reflexes 



102 



TABLE 10-1 



SIGNS THAT DISTINGUISH ORIGIN OF WEAKNESS 



103 



SIGN 


UPPER MOTOR NEURON 


LOWER MOTOR NEURON 


MYOPATHIC 


Atrophy 


None 


Severe 


Mild 


Fasciculations 


None 


Common 


None 


Tone 


Spastic 


Decreased 


Normal/decreased 


Distribution of 


Pyramidal/regional 


Distal/segmental 


Proximal 


weakness 








Tendon reflexes 


Hyperactive 


Hypoactive/absent 


Normal/hypoactive 


Babinski's sign 


Present 


Absent 


Absent 



are generally preserved in patients with myopathic 
weakness except in advanced stages, when they are 
sometimes attenuated. In disorders of the neuromuscular 
junction, the intensity of the reflexes may be affected by 
preceding voluntary activity of affected muscles — such 
activity may lead to enhancement of initially depressed 
reflexes in Lambert-Eaton myasthenic syndrome and, 
conversely, to depression of initially normal reflexes in 
myasthenia gravis (Chap. 42) . 

The distinction of neuropathic (lower motor neuron) 
from myopathic weakness is sometimes difficult clinically, 
although distal weakness is likely to be neuropathic and 
symmetric proximal weakness myopathic. Fasciculations 
(visible or palpable twitch within a muscle due to the 
spontaneous discharge of a motor unit) and early atro- 
phy indicate that weakness is neuropathic. 

PATHOGENESIS 

Upper Motor Neuron Weakness 

This pattern of weakness results from disorders that affect 
the upper motor neurons or their axons in the cerebral 
cortex, subcortical white matter, internal capsule, brain- 
stem, or spinal cord (Fig. 10-1). Such lesions produce 
weakness through decreased activation of the lower 
motor neurons. In general, distal muscle groups are 
affected more severely than proximal ones, and axial 
movements are spared unless the lesion is severe and 
bilateral. With corticobulbar involvement, weakness is 
usually observed only in the lower face and tongue; 
extraocular, upper facial, pharyngeal, and jaw muscles are 
almost always spared. With bilateral corticobulbar lesions, 
pseudobulbar palsy often develops: dysarthria, dysphagia, 
dysphonia, and emotional lability accompany bilateral 
facial weakness and a brisk jaw jerk. Spasticity accompa- 
nies upper motor neuron weakness but may not be pre- 
sent in the acute phase. Upper motor neuron lesions also 
affect the ability to perform rapid repetitive movements. 
Such movements are slow and coarse, but normal rhyth- 
micity is maintained. Finger-nose-finger and heel-knee- 
shin maneuvers are performed slowly but adequately. 



Lower Motor Neuron Weakness 

This pattern results from disorders of cell bodies of 
lower motor neurons in the brainstem motor nuclei and 
the anterior horn of the spinal cord, or from dysfunction 
of the axons of these neurons as they pass to skeletal 
muscle (Fig. 10-2). Weakness is due to a decrease in the 
number of muscle fibers that can be activated, through a 
loss of y motor neurons or disruption of their connec- 
tions to muscle. Loss of y motor neurons does not cause 
weakness but decreases tension on the muscle spindles, 
which decreases muscle tone and attenuates the stretch 
reflexes elicited on examination. An absent stretch reflex 
suggests involvement of spindle afferent fibers. 

When a motor unit becomes diseased, especially in 
anterior horn cell diseases, it may spontaneously dis- 
charge, producing fasciculations that may be seen or felt 
clinically or recorded by electromyography (EMG). 
When OC motor neurons or their axons degenerate, the 
denervated muscle fibers may also discharge sponta- 
neously. These single muscle fiber discharges, or fibrilla- 
tion potentials, cannot be seen or felt but can be recorded 
with EMG. If lower motor neuron weakness is present, 
recruitment of motor units is delayed or reduced, -with 
fewer than normal activated at a given discharge fre- 
quency. This contrasts with weakness of upper motor 
neuron type, in which a normal number of motor units 
is activated at a given frequency but with a diminished 
maximal discharge frequency. 

Myopathic Weakness 

Myopathic weakness is produced by disorders of the 
muscle fibers. Disorders of the neuromuscular junctions 
also produce weakness, but this is variable in degree and 
distribution and is influenced by preceding activity of 
the affected muscle. At a muscle fiber, if the nerve termi- 
nal releases a normal number of acetylcholine molecules 
presynapticalfy and a sufficient number of postsynaptic 
acetylcholine receptors are opened, the end plate 
reaches threshold and thereby generates an action 
potential that spreads across the muscle fiber membrane 



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Corticospinal 
tract 




Red nucleus 
Reticular nuclei 
Vestibular nuclei 
Vestibulospinal tract 

Reticulospinal tract 



Rubrospinal tract 

Lateral corticospinal 
tract 



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Ventromedial 

bulbospinal 

tracts 

FIGURE10-1 

The corticospinal and bulbospinal upper motor neuron 
pathways. Upper motor neurons have their cell bodies in 
layer V of the primary motor cortex (the precentral gyrus, or 
Brodmann's area 4) and in the premotor and supplemental 
motor cortex (area 6). The upper motor neurons in the primary 
motor cortex are somatotopically organized as illustrated on 
the right side of the figure. 

Axons of the upper motor neurons descend through the 
subcortical white matter and the posterior limb of the internal 
capsule. Axons of the pyramidal or corticospinal system 
descend through the brainstem in the cerebral peduncle of 
the midbrain, the basis pontis, and the medullary pyramids. 
At the cervicomedullary junction, most pyramidal axons 
decussate into the contralateral corticospinal tract of the lat- 
eral spinal cord, but 10-30% remains ipsilateral in the ante- 
rior spinal cord. Pyramidal neurons make direct monosynap- 
tic connections with lower motor neurons. They innervate 
most densely the lower motor neurons of hand muscles and 




- Lateral 
corticospinal tract 

Rubrospinal 

(ventrolateral) 

tract 



are involved in the execution of learned, fine movements. 
Corticobulbar neurons are similar to corticospinal neurons 
but innervate brainstem motor nuclei. 

Bulbospinal upper motor neurons influence strength and 
tone but are not part of the pyramidal system. The 
descending ventromedial bulbospinal pathways originate in 
the tectum of the midbrain (tectospinal pathway), the 
vestibular nuclei (vestibulospinal pathway), and the reticular 
formation (reticulospinal pathway). These pathways influ- 
ence axial and proximal muscles and are involved in the 
maintenance of posture and integrated movements of the 
limbs and trunk. The descending ventrolateral bulbospinal 
pathways, which originate predominantly in the red nucleus 
(rubrospinal pathway), facilitate distal limb muscles. The 
bulbospinal system is sometimes referred to as the 
extrapyramidal upper motor neuron system. In all figures, 
nerve cell bodies and axon terminals are shown, respec- 
tively, as closed circles and forks. 



and into the transverse tubular system. This electrical 
excitation activates intracellular events that produce an 
energy-dependent contraction of the muscle fiber (exci- 
tation-contraction coupling) . 

Myopathic weakness is produced by a decrease in the 
number or contractile force of muscle fibers activated 



within motor units. With muscular dystrophies, inflamma- 
tory myopathies, or myopathies with muscle fiber necrosis, 
the number of muscle fibers is reduced within many 
motor units. On EMG, the size of each motor unit action 
potential is decreased, and motor units must be recruited 
more rapidly than normal to produce the desired power. 



Afferent 
neuron 




• 



Alpha and gamma 
motor neurons 



Motor end plates on 
voluntary muscle 
(extrafusal fibers) 



Muscle spindle 
(intrafusal fibers) 

FIGURE 10-2 

Lower motor neurons are divided into (X and y types. The 

larger a motor neurons are more numerous and innervate the 
extrafusal muscle fibers of the motor unit. Loss of a motor 
neurons or disruption of their axons produces lower motor 
neuron weakness. The smaller, less numerous y motor neu- 
rons innervate the intrafusal muscle fibers of the muscle spin- 
dle and contribute to normal tone and stretch reflexes. The oc 
motor neuron receives direct excitatory input from corticomo- 
toneurons and primary muscle spindle afferents. The a and y 
motor neurons also receive excitatory input from other 
descending upper motor neuron pathways, segmental sen- 
sory inputs, and intemeurons. The a motor neurons receive 
direct inhibition from Renshaw cell intemeurons, and other 
intemeurons indirectly inhibit the a and y motor neurons. 

A tendon reflex requires the function of all illustrated struc- 
tures. A tap on a tendon stretches muscle spindles (which 
are tonically activated by y motor neurons) and activates the 
primary spindle afferent neurons. These stimulate the a 
motor neurons in the spinal cord, producing a brief muscle 
contraction, which is the familiar tendon reflex. 



Some myopathies produce weakness through loss of con- 
tractile force of muscle fibers or through relatively selec- 
tive involvement of the type II (fast) fibers. These may not 
affect the size of individual motor unit action potentials 
and are detected by a discrepancy between the electrical 
activity and force of a muscle. 

Diseases of the neuromuscular junction, such as myas- 
thenia gravis, produce weakness in a similar manner, but 
the loss of muscle fibers is functional (due to inability to 
activate them) rather than related to muscle fiber loss. The 
number of muscle fibers that are activated varies over time, 
depending on the state of rest of the neuromuscular junc- 
tions. Thus, fatigable weakness is suggestive of myasthenia 
gravis or other disorders of the neuromuscular junction. 



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Hemiparesis 105 

Hemiparesis results from an upper motor neuron lesion 
above the midcervical spinal cord; most such lesions are 
above the foramen magnum. The presence of other neu- 
rologic deficits helps to localize the lesion. Thus, language 
disorders, cortical sensory disturbances, cognitive abnor- 
malities, disorders of visual-spatial integration, apraxia, or 
seizures point to a cortical lesion. Homonymous visual 
field defects reflect either a cortical or a subcortical hemi- 
spheric lesion. A "pure motor" hemiparesis of the face, 
arm, or leg is often due to a small, discrete lesion in the 
posterior limb of the internal capsule, cerebral peduncle, 
or upper pons. Some brainstem lesions produce "crossed 
paralyses," consisting of ipsilateral cranial nerve signs and 
contralateral hemiparesis. The absence of cranial nerve 
signs or facial weakness suggests that a hemiparesis is due 
to a lesion in the high cervical spinal cord, especially if 
associated with ipsilateral loss of proprioception and con- 
tralateral loss of pain and temperature sense (the Brown- 
Sequard syndrome) . 

Acute or episodic hemiparesis usually results from ischemic 
or hemorrhagic stroke, but may also relate to hemor- 
rhage occurring into brain tumors or as a result of 
trauma; other causes include a focal structural lesion or 
inflammatory process as in multiple sclerosis, abscess, or 
sarcoidosis. Evaluation begins immediately with a CT 
scan of the brain (Fig. 10-3) and laboratory studies. If 
the CT is normal and an ischemic stroke is unlikely, 
MRI of the brain or cervical spine is performed. 

Subacute hemiparesis that evolves over days or weeks 
has an extensive differential diagnosis. A common cause 
is subdural hematoma, especially in elderly or anticoagu- 
lated patients, even when there is no history of trauma. 
Infectious possibilities include cerebral abscess, fungal 
granuloma or meningitis, and parasitic infection. Weak- 
ness from primary and metastatic neoplasms may evolve 
over days to weeks. AIDS may present with subacute 
hemiparesis due to toxoplasmosis or primary CNS lym- 
phoma. Noninfectious inflammatory processes, such as 
multiple sclerosis or, less commonly, sarcoidosis, merit 
consideration. If the brain MRI is normal and there are 
no cortical and hemispheric signs, MRI of the cervical 
spine should be undertaken. 

Chronic hemiparesis that evolves over months is usually 
due to a neoplasm or vascular malformation, a chronic 
subdural hematoma, or a degenerative disease. If an 
MRI of the brain is normal, the possibility of a foramen 
magnum or high cervical spinal cord lesion should be 
considered. 



Paraparesis 

An intraspinal lesion at or below the upper thoracic 
spinal cord level is most commonly responsible, but a 
paraparesis may also result from lesions at other locations 



106 



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Distribution of Weakness 



_ 



Hemiparesis 



X 



Paraparesis 



I 






Quadriparesis 



T 



Monoparesis 



Alert 



UMN signs 



LMN signs* 



Cerebral signs 



X 



(vis) (No) 



f } 

(Ytes) (No) 



Distal 



Proximal 



— 



Restricted 



UMN signs 



UMN signs 



Brain CT 
or MRI f 



LMN signs* 

' 



LMN signs* 



5L 



_r 



UMN pattern 



EMG and NCS 



LMN pattern 



Spinal MRI* 



_ 



3_ 



Myopathic pattern 



Anterior horn, 
root, or peripheral 
nerve disease 



Muscle or 
neuromuscular 
junction disease 



* or signs of myopathy 

f If no abnormality detected, consider spinal MRI. 
If no abnormality detected, consider myelogram or brain MRI. 



FIGURE 10-3 

An algorithm for the initial workup of a patient with 
weakness. EMG, electromyography; LMN, lower motor 



neuron; NCS, nerve conduction studies; UMN, upper motor 
neuron. 






that disturb upper motor neurons (especially parasagittal 
intracranial lesions) and lower motor neurons [anterior 
horn cell disorders, cauda equina syndromes due to 
involvement of nerve roots derived from the lower spinal 
cord (Chap. 30), and peripheral neuropathies]. 

Acute paraparesis may not be recognized as due to 
spinal cord disease at an early stage if the legs are flaccid 
and areflexic. Usually, however, there is sensory loss in 
the legs with an upper level on the trunk; a dissociated 
sensory loss suggestive of a central cord syndrome; or 
exaggerated stretch reflexes in the legs with normal 
reflexes in the arms. It is important to image the spinal 
cord (Fig. 10-3). Compressive lesions (particularly epidural 
tumor, abscess, or hematoma, but also a prolapsed inter- 
vertebral disk and vertebral involvement by malignancy 
or infection), spinal cord infarction (proprioception is 
usually spared), an arteriovenous fistula or other vascular 
anomaly, and transverse myelitis, are among the possible 
causes (Chap. 30). 

Diseases of the cerebral hemispheres that produce 
acute paraparesis include anterior cerebral artery ischemia 
(shoulder shrug is also affected), superior sagittal sinus or 
cortical venous thrombosis, and acute hydrocephalus. If 
upper motor neuron signs are associated with drowsiness, 



confusion, seizures, or other hemispheric signs, MRI of 
the brain should be undertaken. 

Paraparesis may result from a cauda equina syndrome, 
for example, following trauma to the low back, a mid- 
line disk herniation, or an intraspinal tumor; although 
sphincters are affected, hip flexion is often spared, as is 
sensation over the anterolateral thighs. Rarely, paraparesis 
is caused by a rapidly evolving anterior horn cell disease 
(such as poliovirus or West Nile virus infection), periph- 
eral neuropathy (such as Guillain-Barre syndrome; 
Chap. 41) or myopathy (Chap. 43). In such cases, elec- 
trophysiologic studies are diagnostically helpful and 
refocus the subsequent evaluation. 

Subacute or chronic paraparesis with spasticity is caused 
by upper motor neuron disease. When there is associ- 
ated lower-limb sensory loss and sphincter involvement, 
a chronic spinal cord disorder is likely (Chap. 30). If an 
MRI of the spinal cord is normal, MRI of the brain 
may be indicated. If hemispheric signs are present, a 
parasagittal meningioma or chronic hydrocephalus is 
likely and MRI of the brain is the initial test. In the 
rare situation in which a longstanding paraparesis has a 
lower motor neuron or myopathic etiology, the local- 
ization is usually suspected on clinical grounds by the 



absence of spasticity and confirmed by EMG and nerve 
conduction tests. 

Quadriparesis or Generalized Weakness 

Generalized weakness may be due to disorders of the 
CNS or of the motor unit. Although the terms quadripare- 
sis and generalized weakness are often used interchangeably, 
quadriparesis is commonly used when an upper motor 
neuron cause is suspected, and generalized weakness 
when a disease of the motor unit is likely. Weakness from 
CNS disorders is usually associated with changes in con- 
sciousness or cognition, with spasticity and brisk stretch 
reflexes, and with alterations of sensation. Most neuro- 
muscular causes of generalized weakness are associated 
with normal mental function, hypotonia, and hypoactive 
muscle stretch reflexes. The major causes of intermittent 
weakness are listed in Table 10-2. A patient with general- 
ized fatigability without objective weakness may have the 
chronic fatigue syndrome (Chap. 47) . 

^H Acute Quadriparesis 

Acute quadriparesis with onset over minutes may result 
from disorders of upper motor neurons (e.g., anoxia, 
hypotension, brainstem or cervical cord ischemia, trauma, 
and systemic metabolic abnormalities) or muscle (elec- 
trolyte disturbances, certain inborn errors of muscle 
energy metabolism, toxins, or periodic paralyses). Onset 
over hours to weeks may, in addition to the above, be due 
to lower motor neuron disorders. Guillain-Barre syn- 
drome (Chap. 41) is the most common lower motor neu- 
ron weakness that progresses over days to 4 weeks; the 
finding of an elevated protein level in the cerebrospinal 
fluid is helpful but may be absent early in the course. 

In obtunded patients, evaluation begins with a CT 
scan of the brain. If upper motor neuron signs are present 



TABLE 10-2 



CAUSES OF EPISODIC GENERALIZED WEAKNESS 



Electrolyte disturbances, e.g., hypokalemia, 
hyperkalemia, hypercalcemia, hypernatremia, 
hyponatremia, hypophosphatemia, hypermagnesemia 
Muscle disorders 

a. Channelopathies (periodic paralyses) 

b. Metabolic defects of muscle (impaired carbohydrate 
or fatty acid utilization; abnormal mitochondrial 
function) 

Neuromuscular junction disorders 

a. Myasthenia gravis 

b. Lambert-Eaton myasthenic syndrome 
Central nervous system disorders 

a. Transient ischemic attacks of the brainstem 

b. Transient global cerebral ischemia 

c. Multiple sclerosis 



but the patient is alert, the initial test is usually an MRI 107 
of the cervical cord. If weakness is lower motor neuron, 
myopathic, or uncertain in origin, the clinical approach 
begins with blood studies to determine the level of 
muscle enzymes and electrolytes and an EMG and nerve 
conduction study. 



^B Subacute or Chronic Quadriparesis 

When quadriparesis due to upper motor neuron disease 
develops over weeks, months, or years, the distinction 
between disorders of the cerebral hemispheres, brain- 
stem, and cervical spinal cord is usually possible clinically. 
An MRI is obtained of the clinically suspected site of 
pathology. EMG and nerve conduction studies help to 
distinguish lower motor neuron disease (which usually 
presents -with weakness that is most profound distally) 
from myopathic weakness, which is typically proximal. 



Monoparesis 

This is usually due to lower motor neuron disease, with 
or without associated sensory involvement. Upper 
motor neuron weakness occasionally presents as a 
monoparesis of distal and nonantigravity muscles. Myo- 
pathic weakness is rarely limited to one limb. 

^H Acute Monoparesis 

If the weakness is predominantly in distal and nonanti- 
gravity muscles and not associated with sensory impair- 
ment or pain, focal cortical ischemia is likely (Chap. 21); 
diagnostic possibilities are similar to those for acute hemi- 
paresis. Sensory loss and pain usually accompany acute 
lower motor neuron weakness; the weakness is commonly 
localized to a single nerve root or peripheral nerve within 
the limb but occasionally reflects plexus involvement. If 
lower motor neuron weakness is suspected, or the pattern 
of weakness is uncertain, the clinical approach begins 
with an EMG and nerve conduction study. 

^H Subacute or Chronic Monoparesis 

Weakness and atrophy that develop over weeks or 
months are usually of lower motor neuron origin. If 
they are associated with sensory symptoms, a peripheral 
cause (nerve, root, or plexus) is likely; in the absence of 
such symptoms, anterior horn cell disease should be 
considered. In either case, an electrodiagnostic study is 
indicated. If weakness is of upper motor neuron type, a 
discrete cortical (precentral gyrus) or cord lesion may be 
responsible, and an imaging study is performed of the 
appropriate site. 

Distal Weakness 

Involvement of two or more limbs distally suggests 
lower motor neuron or peripheral nerve disease. Acute 



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distal lower limb weakness occurs occasionally from an 
acute toxic polyneuropathy or cauda equina syndrome. 
Distal symmetric weakness usually develops over weeks, 
months, or years and, when associated with numbness, is 
due to metabolic, toxic, hereditary, degenerative, or 
inflammatory diseases of peripheral nerves (Chap. 40). 
Anterior horn cell disease may begin distally but is typi- 
cally asymmetric and without accompanying numbness 
(Chap. 27). Rarely, myopathies present with distal weak- 
ness (Chap. 43) . Electrodiagnostic studies help to localize 
the disorder (Fig. 10-3). 

Proximal Weakness 

Myopathy often produces symmetric weakness of the 
pelvic or shoulder girdle muscles (Chap. 43). Diseases of 
the neuromuscular junction [such as myasthenia gravis 
(Chap. 42)], may present with symmetric proximal 
weakness often associated with ptosis, diplopia, or bulbar 
weakness and fluctuating in severity during the day. 
Extreme fatigability present in some cases of myasthenia 
gravis may even suggest episodic weakness, but strength 
rarely returns fully to normal. In anterior horn cell dis- 
ease proximal weakness is usually asymmetric, but may 
be symmetric if familial. Numbness does not occur with 
any of these diseases. The evaluation usually begins with 
determination of the serum creatine kinase level and 
electrophysiologic studies. 



Weakness in a Restricted Distribution 

Weakness may not fit any of the above patterns, being 
limited, for example, to the extraocular, hemifacial, bul- 
bar, or respiratory muscles. If unilateral, restricted weak- 
ness is usually due to lower motor neuron or peripheral 
nerve disease, such as in a facial palsy (Chap. 29) or an 
isolated superior oblique muscle paresis (Chap. 17). 
Weakness of part of a limb is usually due to a peripheral 
nerve lesion such as carpal tunnel syndrome or another 
entrapment neuropathy. Relatively symmetric weakness 
of extraocular or bulbar muscles is usually due to a 
myopathy (Chap. 43) or neuromuscular junction disor- 
der (Chap. 42). Bilateral facial palsy with areflexia sug- 
gests Guillain-Barre syndrome (Chap. 41). Worsening of 
relatively symmetric weakness with fatigue is character- 
istic of neuromuscular junction disorders. Asymmetric 
bulbar weakness is usually due to motor neuron disease. 
Weakness limited to respiratory muscles is uncommon 
and is usually due to motor neuron disease, myasthenia 
gravis, or polymyositis/dermatomyositis (Chap. 44). 

Acknowledgment 

Richard K. Olney, MD, was the author of this chapter 
in previous editions, and his contributions in the last three 
editions of Harrison's Principles of Internal Medicine are 
appreciated. 







Lewis Sudarsky 



Prevalence, Morbidity, and Mortality 1 09 

Anatomy and Physiology 1 09 

Disorders of Gait 110 

Disorders of Balance 113 

Falls 113 

Further Readings 115 



PREVALENCE, MORBIDITY, AND 
MORTALITY 

Gait and balance problems are common in the elderly 
and contribute to the risk of falls and injury. Gait disor- 
ders have been described in 1 5% of individuals older than 
65 years. By 80 years, one person in four will use a 
mechanical aid to assist ambulation. Among those 85 years 
and older, the prevalence of gait abnormality approaches 
40%. In epidemiologic studies, gait disorders are consis- 
tendy identified as a major risk factor for falls and injury. 
A substantial number of older persons report insecure 
balance and experience falls and fear of falling. Prospec- 
tive studies indicate that 20—30% of individuals >65 years 
fall each year, and the proportion is even higher in hos- 
pitalized elderly and nursing home patients. Each year 
8% of individuals >75 years suffer a serious fall-related 
injury. Hip fractures often result in hospitalization and 
nursing home admission. For each person who is physi- 
cally disabled, there are others whose functional inde- 
pendence is constrained by anxiety and fear of falling. 
Nearly one in five of elderly individuals voluntarily 
limit their activity because of fear of falling. With loss of 
ambulation, there is a diminished quality of life and 
increased morbidity and mortality. 

ANATOMY AND PHYSIOLOGY 

Upright bipedal gait depends on the successful integra- 
tion of postural control and locomotion. These functions 



are widely distributed in the central nervous system. The 
biomechanics of bipedal walking are complex, and the 
performance is easily compromised by injury at any 
level. Command and control centers in the brainstem, 
cerebellum, and forebrain modify the action of spinal 
pattern generators to promote stepping. While a form of 
"fictive locomotion" can be elicited from quadrupedal 
animals after spinal transection, this capacity is limited in 
primates. Step generation in primates is dependent on 
locomotor centers in the pontine tegmentum, midbrain, 
and subthalamic region. Locomotor synergies are exe- 
cuted through the reticular formation and descending 
pathways in the ventromedial spinal cord. Cerebral con- 
trol provides a goal and purpose for walking and is involved 
in avoidance of obstacles and adaptation of locomotor 
programs to context and terrain. 

Postural control requires the maintenance of the cen- 
ter of mass over the base of support through the gait 
cycle. Unconscious postural adjustments maintain stand- 
ing balance: long latency responses are measurable in the 
leg muscles, beginning 110 ms after a perturbation. For- 
ward motion of the center of mass provides propulsive 
force for stepping, but failure to maintain the center of 
mass within stability limits results in falls. The anatomic 
substrate for dynamic balance has not been well defined, 
but the vestibular nucleus and midline cerebellum con- 
tribute to balance control in animals. Human patients 
with damage to these structures have impaired balance 
with standing and walking. 



109 



110 



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Standing balance depends on good quality sensory 
information about the position of the body center with 
respect to the environment, support surface, and gravita- 
tional forces. Sensory information for postural control is 
primarily generated by the visual system, the vestibular 
system, and by proprioceptive receptors in the muscle 
spindles and joints. A healthy redundancy of sensory 
afferent information is generally available, but loss of 
two of the three pathways is sufficient to compromise 
standing balance. Balance disorders in older individuals 
sometimes result from multiple insults in the peripheral 
sensory systems (e.g., visual loss, vestibular deficit, 
peripheral neuropathy), critically degrading the quality 
of afferent information needed for balance stability. 

Older patients with mental status abnormalities and 
dementia from neurodegenerative diseases appear to be 
particularly prone to falls and injury. Frailty, muscle weak- 
ness, and deconditioning undoubtedly contribute to the 
risk. There is a growing literature on the use of attentional 
resources to manage locomotion. The ability to walk 
while attending to a cognitive task (dual tasking) may be 
particularly compromised in older adults with a history of 
falls. Walking is generally considered to be unconscious 
and automatic, but older patients with deficits in execu- 
tive function may be unable to manage the attention 
needed for dynamic balance when distracted. 

DISORDERS OF GAIT 

The heterogeneity of gait disorders observed in clinical 
practice reflects the large network of neural systems 
involved in the task. There is the potential for abnor- 
malities to develop, and walking is vulnerable to neuro- 
logic disease at every level. Gait disorders have been 
classified descriptively, based on the abnormal physiol- 
ogy and biomechanics. One problem with this approach 
is that many failing gaits look fundamentally similar. 
This overlap reflects common patterns of adaptation to 
threatened balance stability and declining performance. 
The gait disorder observed clinically must be viewed as the 
product of a neurologic deficit and a functional adaptation. 
Unique features of the failing gait are often over- 
whelmed by the adaptive response. Some of the com- 
mon patterns of abnormal gait are summarized below. 
Gait disorders can also be classified by etiology, as listed 
in Table 11-1. 

Cautious Gait 

The term cautious gait is used to describe the patient 
who walks with an abbreviated stride and lowered center 
of mass, as if walking on a slippery surface. This disorder 
is both common and nonspecific. It is, in essence, an 
adaptation to a perceived postural threat. A fear of falling 
may be associated. In one study, this disorder was observed 
in more than one-third of older patients with a higher 



TABLE 11-1 



ETIOLOGY OF GAIT DISORDER 





CASES 


PERCENT 


Sensory deficits 


22 


18.3 


Myelopathy 


20 


16.7 


Multiple infarcts 


18 


15.0 


Parkinsonism 


14 


11.7 


Cerebellar degeneration 


8 


6.7 


Hydrocephalus 


8 


6.7 


Toxic/metabolic 


3 


2.5 


Psychogenic 


4 


3.3 


Other 


6 


5.0 


Unknown cause 
Total 


17 


14.2 


120 


100% 



Source: Reproduced with permission from Masdeu et al. 



level gait disturbance. Physical therapy often improves 
walking to the degree that follow-up observation may 
reveal a more specific underlying disorder. 

Stiff-Legged Gait 

Spastic gait is characterized by stiffness in the legs, an 
imbalance of muscle tone, and a tendency to circumduct 
and scuff the feet. The disorder reflects compromise of 
corticospinal command and overactivity of spinal 
reflexes. The patient may walk on his or her toes. In 
extreme instances, the legs cross due to increased tone in 
the adductors. Upper motor neuron signs are present on 
physical examination. Shoes often reflect an uneven pat- 
tern of wear across the outside. The disorder may be 
cerebral or spinal in origin. 

Myelopathy from cervical spondylosis is a common 
cause of spastic or spastic-ataxic gait. Demyelinating dis- 
ease and trauma are the leading causes of myelopathy in 
younger patients. In a chronic progressive myelopathy of 
unknown cause, workup with laboratory and imaging 
tests may establish a diagnosis of multiple sclerosis. A 
family history should suggest hereditary spastic paraple- 
gia (HSP). Genetic testing is now available for some of 
the common HSP mutations. Tropical spastic paraparesis 
related to the retrovirus HTLV-I is endemic in parts of 
the Caribbean and South America. A structural lesion, 
such as tumor or spinal vascular malformation, should 
be excluded with appropriate testing. Spinal cord disor- 
ders are discussed in detail in Chap. 30. 

With cerebral spasticity asymmetry is common, involve- 
ment of the upper extremities is usually observed, and 
dysarthria is often an associated feature. Common causes 
include vascular disease (stroke), multiple sclerosis, and 
perinatal injury to the nervous system (cerebral palsy). 

Other stiff-legged gaits include dystonia (Chap. 25) and 
stiff-person syndrome. Dystonia is a disorder characterized 



by sustained muscle contractions, resulting in repetitive 
twisting movements and abnormal posture. It often has a 
genetic basis. Dystonic spasms produce plantar flexion 
and inversion of the feet, sometimes with torsion of the 
trunk. In autoimmune stiff-person syndrome, there is 
exaggerated lordosis of the lumbar spine and overactiva- 
tion of antagonist muscles, which restricts trunk and 
lower limb movement and results in a wooden or fixed 
posture. 

Parkinsonism and Freezing Gait 

Parkinson's disease (Chap. 24) is common, affecting 1% 
of the population >55 years. The stooped posture and 
shuffling gait are characteristic and distinctive features. 
Patients sometimes accelerate (festinate) with walking or 
display retropulsion. There may be difficulty with gait 
initiation (freezing) and a tendency to turn en bloc. 
Imbalance and falls may develop as the disease progresses 
over years. Other progressive neurodegenerative disorders 
may also involve a freezing gait; these include progressive 
supranuclear palsy, multiple system atrophy, corticobasal 
degeneration, and primary pallidal degeneration. Such 
patients with atypical parkinsonian syndromes frequently 
present with axial stiffness, postural instability, and a 
shuffling gait but tend to lack the characteristic pill-rolling 
tremor of Parkinson's disease. Falls within the first year 
suggest the possibility of progressive supranuclear palsy. 
Hyperkinetic movement disorders also produce char- 
acteristic and recognizable disturbances in gait. In Hunt- 
ington's disease (Chap. 25), the unpredictable occurrence 
of choreic movements gives the gait a dancing quality. 
Tardive dyskinesia is the cause of many odd, stereotypic 
gait disorders seen in chronic psychiatric patients. 

Frontal Gait Disorder 

Frontal gait disorder, sometimes known as "gait apraxia," 
is common in the elderly and has a variety of causes. 
Typical features include a wide base of support, short 
stride, shuffling along the floor, and difficulty with starts 
and turns. Many patients exhibit difficulty with gait ini- 
tiation, descriptively characterized as the "slipping 
clutch" syndrome or "gait ignition failure." The term 
lower body parkinsonism is also used to describe such 
patients. Strength is generally preserved, and patients are 
able to make stepping movements when not standing 
and maintaining balance at the same time. This disorder 
is a higher level motor control disorder, as opposed to an 
apraxia. 

The most common cause of frontal gait disorder is 
vascular disease, particularly subcortical small-vessel dis- 
ease. Lesions are frequently found in the deep frontal 
white matter and centrum ovale. Gait disorder may be 
the salient feature in hypertensive patients with ischemic 
lesions of the deep hemisphere white matter (Binswanger's 



disease) . The clinical syndrome includes mental change T| 1 
(variable in degree), dysarthria, pseudobulbar affect (emo- 
tional disinhibition), increased tone, and hyperreflexia in 
the lower limbs. 

Communicating hydrocephalus in the adult also pre- 
sents with a gait disorder of this type. Other features of 
the diagnostic triad (mental change, incontinence) may 
be absent in the initial stages. MRI demonstrates ven- 
tricular enlargement, an enlarged flow void about the 
aqueduct, and a variable degree of periventricular white 
matter change. A lumbar puncture or dynamic test is 
necessary to confirm the presence of hydrocephalus. 

Cerebellar Gait Ataxia 



Disorders of the cerebellum have a dramatic impact on 
gait and balance. Cerebellar gait ataxia is characterized 
by a wide base of support, lateral instability of the trunk, 
erratic foot placement, and decompensation of balance 
when attempting to -walk tandem. Difficulty maintain- 
ing balance -when turning is often an early feature. 
Patients are unable to walk tandem heel to toe, and dis- 
play truncal sway in narrow-based or tandem stance. 
They show considerable variation in their tendency to 
fall in daily life. 

Causes of cerebellar ataxia in older patients include 
stroke, trauma, tumor, and neurodegenerative disease, 
including multiple system atrophy (Chaps. 24 and 26) 
and various forms of hereditary cerebellar degeneration 
(Chap. 24). MRI demonstrates the extent and topogra- 
phy of cerebellar atrophy. A short expansion at the site 
of the fragile X mutation (fragile X pre-mutation) has 
been associated with gait ataxia in older men. Alcoholic 
cerebellar degeneration can be screened by history and 
often confirmed by MRI. 

Sensory Ataxia 

As reviewed above, balance depends on high-quality 
afferent information from the visual and the vestibular 
systems and proprioception. When this information is 
lost or degraded, balance during locomotion is impaired 
and instability results. The sensory ataxia of tabetic neu- 
rosyphilis is a classic example. The contemporary equiva- 
lent is the patient with neuropathy affecting large fibers. 
Vitamin B 12 deficiency is a treatable cause of large-fiber 
sensory loss in the spinal cord and peripheral nervous 
system. Joint position and vibration sense are diminished 
in the lower limbs. The stance in such patients is destabi- 
lized by eye closure; they often look down at their feet 
when walking and do poorly in the dark. Patients have 
been described with imbalance from bilateral vestibular 
loss, caused by disease or by exposure to ototoxic drugs. 
Table 11-2 compares sensory ataxia with cerebellar ataxia 
and frontal gait disorder. Some patients exhibit a syndrome 
of imbalance from the combined effect of multiple sensory 



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TABLE 11-2 



FEATURES OF CEREBELLAR ATAXIA, SENSORY ATAXIA, AND FRONTAL GAIT DISORDERS 





CEREBELLAR ATAXIA 


SENSORY ATAXIA 


FRONTAL GAIT 


Base of support 


Wide-based 




Narrow base, looks down 


Wide-based 


Velocity 


Variable 




Slow 


Very slow 


Stride 


Irregular, lurch 


ing 


Regular with path 
deviation 


Short, shuffling 


Romberg 


+/- 




Unsteady, falls 


+/- 


Heel — > shin 


Abnormal 




+/- 


Normal 


Initiation 


Normal 




Normal 


Hesitant 


Turns 


Unsteady 




+/- 


Hesitant, multistep 


Postural instability 


+ 




+++ 


++++ 

Poor postural synergies 
getting up from a chair 


Falls 


Late event 




Frequent 


Frequent 



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deficits. Such patients, often elderly and diabetic, have 
disturbances in proprioception, vision, and vestibular 
sense that impair postural support. 

Neuromuscular Disease 

Patients with neuromuscular disease often have an abnor- 
mal gait, occasionally as a presenting feature. With distal 
weakness (peripheral neuropathy) the step height is 
increased to compensate for foot drop, and the sole of 
the foot may slap on the floor during weight acceptance. 
Neuropathy may be associated with a degree of sensory 
imbalance, as described earlier. Patients with myopathy or 
muscular dystrophy more typically exhibit proximal 
weakness. Weakness of the hip girdle may result in a 
degree of excess pelvic sway during locomotion. 



patients with extreme anxiety or phobia walk with 
exaggerated caution with abduction of the arms, as if 
walking on ice. This inappropriately overcautious gait 
differs in degree from the gait of the patient who is 
insecure and making adjustments for imbalance. 
Depressed patients exhibit primarily slowness, a manifes- 
tation of psychomotor retardation, and lack of purpose 
in their stride. Hysterical gait disorders are among the 
most spectacular encountered. Odd gyrations of posture 
with wastage of muscular energy (astasia-abasia), 
extreme slow motion, and dramatic fluctuations over 
time may be observed in patients with somatoform dis- 
orders and conversion reaction. 



Toxic and Metabolic Disorders 

Alcohol intoxication is the most common cause of acute 
walking difficulty Chronic toxicity from medications 
and metabolic disturbances can impair motor function 
and gait. Mental status changes may be present, and 
examination may reveal asterixis or myoclonus. Static 
equilibrium is disturbed, and such patients are easily 
thrown off balance. Disequilibrium is particularly evi- 
dent in patients with chronic renal disease and those 
with hepatic failure, in whom asterixis may impair pos- 
tural support. Sedative drugs, especially neuroleptics and 
long-acting benzodiazepines, affect postural control and 
increase the risk for falls. These disorders are important 
to recognize because they are often treatable. 

Psychogenic Gait Disorder 

Psychogenic disorders are common in outpatient prac- 
tice, and the presentation often involves gait. Some 



Approach to the Patient: 

SLOWLY PROGRESSIVE DISORDER OF GAIT 

When reviewing the history it is helpful to inquire 
about the onset and progression of disability. Initial 
awareness of an unsteady gait often follows a fall. 
Stepwise evolution or sudden progression suggest vas- 
cular disease. Gait disorder may be associated with 
urinary urgency and incontinence, particularly in 
patients with cervical spine disease or hydrocephalus. 
It is always important to review the use of alcohol 
and medications that affect gait and balance. Informa- 
tion on localization derived from the neurologic 
examination can be helpful to narrow the list of pos- 
sible diagnoses. 

Gait observation provides an immediate sense of 
the patient's degree of disability. Characteristic pat- 
terns of abnormality are sometimes observed, though 
failing gaits often look fundamentally similar. Cadence 



(steps/min), velocity, and stride length can be recorded 
by timing a patient over a fixed distance. Watching 
the patient get out of a chair provides a good func- 
tional assessment of balance. 

Brain imaging studies may be informative in patients 
with an undiagnosed disorder of gait. MRI is sensitive 
for cerebral lesions of vascular or demyelinating disease 
and is a good screening test for occult hydrocephalus. 
Patients with recurrent falls are at risk for subdural 
hematoma. Many elderly patients with gait and balance 
difficulty have white matter abnormalities in the 
periventricular region and centrum semiovale. While 
these lesions may be an incidental finding, a substantial 
burden of white matter disease will ultimately impact 
cerebral control of locomotion. 



DISORDERS OF BALANCE 

Balance is the ability to maintain equilibrium: a state in 
which opposing physical forces cancel. In physiology, 
this is taken to mean the ability of the organism to con- 
trol the center of mass with respect to gravity and the 
support surface. In reality, no one is aware of what or 
where the center of mass is, but everyone, including 
gymnasts, figure skaters, and platform divers, move so as 
to manage it. Imbalance implies a disturbance of equi- 
librium. Disorders of balance present with difficulty 
maintaining posture standing and walking and with a 
subjective sense of disequilibrium, a form of dizziness. 

The cerebellum and vestibular system organize anti- 
gravity responses needed to maintain the upright pos- 
ture. As reviewed earlier, these responses are physiologi- 
cally complex, and the anatomic representation is not 
well understood. Failure, resulting in disequilibrium, can 
occur at several levels: cerebellar, vestibular, somatosen- 
sory, and higher level disequilibrium. Patients with 
hereditary ataxia or alcoholic cerebellar degeneration do 
not generally complain of dizziness, but balance is visi- 
bly impaired. Neurologic examination will reveal a vari- 
ety of cerebellar signs. Postural compensation may pre- 
vent falls early on, but falls inevitably occur with disease 
progression. The progression of a neurodegenerative 
ataxia is often measured by the number of years to loss 
of stable ambulation. Vestibular disorders have symptoms 
and signs in three categories: vertigo, the subjective 
appreciation or illusion of movement; nystagmus, a 
vestibulo-oculomotor sign; and poor balance, an impair- 
ment of vestibulospinal function. Not every patient has 
all manifestations. Patients with vestibular deficits related 
to ototoxic drugs may lack vertigo or obvious nystag- 
mus, but balance is impaired on standing and walking, 
and the patient cannot navigate in the dark. Laboratory 
testing is available to explore vestibulo-oculomotor and 
vestibulospinal deficits. 



Somatosensory deficits also produce imbalance and 
falls. There is often a subjective sense of insecure balance 
and fear of falling. Postural control is compromised by 
eye closure (Romberg's sign); these patients also have dif- 
ficulty navigating in the dark. A dramatic example is the 
patient with autoimmune subacute sensory neuropathy, 
sometimes a paraneoplastic disorder (Chap. 39). Com- 
pensatory strategies enable such patients to walk in the 
virtual absence of proprioception, but the task requires 
active visual monitoring. Patients with higher level disor- 
ders of equilibrium have difficulty maintaining balance 
in daily life and may present with falls. There may be 
reduced awareness of balance impairment. Classic exam- 
ples include patients -with progressive supranuclear palsy 
and normal pressure hydrocephalus. Patients on sedating 
medications are also in this category. In prospective stud- 
ies, cognitive impairment and the use of sedative medica- 
tions substantially increase the risk for falls. 

FALLS 

Falls are a common event, particularly among the 
elderly. Modest changes in balance function have been 
described in fit older subjects as a result of normal 
aging. Subtle deficits in sensory systems, attention, and 
motor reaction time contribute to the risk, and environ- 
mental hazards abound. Epidemiologic studies have 
identified a number of risk factors for falls, summarized 
in Table 11-3. A fall is not a neurologic problem, nor 
reason for referral to a specialist, but there are circum- 
stances in which neurologic evaluation is appropriate. In 
a classic study, 90% of fall events occurred among 10% 
of individuals, a group known as recurrent fallen. Some of 
these are frail older persons with chronic diseases. 
Recurrent falls sometimes indicate the presence of seri- 
ous balance impairment. Syncope, seizure, or falls related 
to loss of consciousness require appropriate evaluation 
and treatment (Chaps. 8 and 20). 



TABLE 11-3 



RISK FACTORS FOR FALLS, A META-ANALYSIS: 
SUMMARY OF SIXTEEN CONTROLLED STUDIES 



113 



RISK FACTOR 


MEAN RR (OR) 


RANGE 


Weakness 


4.9 


1.9-10.3 


Balance deficit 


3.2 


1.6-5.4 


Gait disorder 


3.0 


1 .7-4.8 


Visual deficit 


2.8 


1.1-7.4 


Mobility limitation 


2.5 


1.0-5.3 


Cognitive impairment 


2.4 


2.0-4.7 


Impaired functional status 


2.0 


1.0-3.1 


Postural hypotension 


1.9 


1.0-3.4 



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Note: RR, relative risks from prospective studies; OR, odds ratios 

from retrospective studies. 

Source: Reprinted from Masdeu et al, with permission. 



114 The descriptive classification of falls is as difficult as 
the classification of gait disorders, for many of the same 
reasons. Postural control systems are widely distributed, 
and a number of disease-related abnormalities occur. 
Unlike gait problems that are apparent on observation, 
falls are rarely observed in the office. The patient and 
family may have limited information about what trig- 
gered the fall. Injuries can complicate the physical 
examination. Although there is no standard nosology of 
falls, common patterns can be identified. 

|2l Slipping, Tripping, and "Mechanical Falls" 

Slipping on icy pavement, tripping on obstacles, and falls 
related to obvious environmental factors are often 
termed mechanical falls. They occasionally occur in 
healthy individuals with good balance compensation. 
Frequent tripping falls raise suspicion about an underly- 
ing neurologic deficit. Patients with spasticity, leg weak- 
ness, or foot drop experience tripping falls. 



S Weakness and Frailty 

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5? Patients who lack strength in antigravity muscles have 

S, difficulty rising from a chair, fatigue easily when walk- 
^ ing, and have difficulty maintaining their balance after a 
^ perturbation. These patients are often unable to get up 
after a fall and may be on the floor for an hour or more 
before help arrives. Deconditioning of this sort is often 
treatable. Resistance strength training can increase mus- 
cle mass and leg strength in people in their 80s and 90s. 



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Drop Attacks and Collapsing Falls 

Drop attacks are sudden collapsing falls without loss of 
consciousness. Patients who collapse from lack of pos- 
tural tone present a diagnostic challenge. The patient may 
report that his or her legs just gave out underneath; the 
family may describe the patient as "collapsing in a heap." 
Orthostatic hypotension may be a factor in some such 
falls. Asterixis or epilepsy may impair postural support. 
A colloid cyst of the third ventricle can present with inter- 
mittent obstruction of the foramen of Monroe, resulting in 
a drop attack. While collapsing falls are more common in 
older patients with vascular risk factors, they should not be 
confused with vertebrobasilar ischemic attacks. 



Toppling Falls 

Some patients maintain tone in antigravity muscles but 
fall over like a tree trunk, as if postural defenses had disen- 
gaged. There may be a consistent direction to such falls. 
The patient with cerebellar pathology may lean and top- 
ple over toward the side of the lesion. Patients with 
lesions of the vestibular system or its central pathways 
may experience lateral pulsion and toppling falls. Patients 
with progressive supranuclear palsy often fall over backwards. 



Falls of this nature occur in patients with advanced 
Parkinson's disease once postural instability has developed. 

Gait Freezing 

Another fall pattern in Parkinson's disease and related 
disorders is the fall due to freezing of gait. The feet stick 
to the floor and the center of mass keeps moving, result- 
ing in a disequilibrium from which the patient cannot 
recover. This can result in a forward fall. Gait freezing 
can also occur as the patient attempts to turn and 
change direction. Similarly, the patient with Parkinson's 
disease and festinating gait may find his feet unable to 
keep up, resulting in a forward fall. 

Falls Related to Sensory Deficit 

Patients with somatosensory, visual, or vestibular deficits 
are prone to falls. These patients have particular difficulty 
dealing with poor illumination or walking on uneven 
ground. These patients often express subjective imbalance, 
apprehension, and fear of falling. Deficits in joint position 
and vibration sense are apparent on physical examination. 



Treatment: 
[T INTERVENTIONS TO REDUCE 

THE RISK OF FALLS AND INJURY 

Efforts should be made to define the etiology of the gait 
disorder and mechanism of the falls. Standing blood 
pressure should be recorded. Specific treatment may be 
possible, once a diagnosis is established. Therapeutic 
intervention is often recommended for older patients at 
substantial risk for falls, even if no neurologic disease is 
identified. A home visit to look for environmental hazards 
can be helpful. A variety of modifications may be recom- 
mended to improve safety, including improved lighting 
and the installation of grab bars and nonslip surfaces. 

Rehabilitation interventions attempt to improve muscle 
strength and balance stability and to make the patient 
more resistant to injury. High-intensity resistance strength 
training with weights and machines is useful to improve 
muscle mass, even in frail older patients. Improvements 
are realized in posture and gait, which should translate to 
reduced risk of falls and injury. The goal of sensory bal- 
ance training is to improve balance stability. Measurable 
gains can be achieved in a few weeks of training, and 
benefits can be maintained over 6 months by a 10- to 
20-min home exercise program.This strategy is particularly 
successful in patients with vestibular and somatosensory 
balance disorders. The Yale Health and Aging study used 
a strategy of targeted, multiple risk factor abatement to 
reduce falls in the elderly. Prescription medications were 
adjusted, and home-based exercise programs were 



tailored to the patient's need, based on an initial geriatric 
assessment. The program realized a 44% reduction in 
falls, in comparison with a control group of patients who 
had periodic social visits. 



FURTHER READINGS 

BlSCHOFF-FERRARI HA et al: Fall prevention with supplemental and 
active forms of vitamin D: a meta-analysis of randomised controlled 
trials. BMJ 339:3692, 2009 



Bronstein A et al: Clinical Disorders of Balance, Posture and Gait. 

London, Arnold Press, 2003 
Ganz DA et al:Will my patient fall? JAMA 297:77, 2007 
Horlings CG et al: A weak balance: the contribution of muscle 

weakness to postural instability and falls. Nat Clin Pract Neurol 

4:504, 2008 
MASDEU J et al: Gait Disorders of Aging: With Special Reference to Falls. 

Boston, Little Brown, 1995 
SNIJDERS AH et al: Neurological gait disorders in elderly people: 

Clinical approach and classification. Lancet Neurol 6:63, 2007 
TlNETTI ME: Preventing falls in elderly persons. N Engl J Med 

348:42, 2003 



115 



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Michael J. Aminoff ■ Arthur K. Asbury 



Positive and Negative Symptoms 116 

Terminology 116 

Anatomy of Sensation 117 

Examination of Sensation 118 

Localization of Sensory Abnormalities 1 20 



Normal somatic sensation reflects a continuous moni- 
toring process, little of which reaches consciousness 
under ordinary conditions. By contrast, disordered sen- 
sation, particularly when experienced as painful, is 
alarming and dominates the sufferer's attention. Physi- 
cians should be able to recognize abnormal sensations by 
how they are described, know their type and likely site 
of origin, and understand their implications. Pain is con- 
sidered separately in Chap. 5. 

POSITIVE AND NEGATIVE SYMPTOMS 

Abnormal sensory symptoms may be divided into two 
categories, positive and negative. The prototypical posi- 
tive symptom is tingling (pins-and-needles); other posi- 
tive sensory phenomena include altered sensations that 
are described as pricking, bandlike, lightning-like shoot- 
ing feelings (lancinations), aching, knifelike, twisting, 
drawing, pulling, tightening, burning, searing, electrical, 
or raw feelings. Such symptoms are often painful. 

Positive phenomena usually result from trains of 
impulses generated at sites of lowered threshold or 
heightened excitability along a peripheral or central 
sensory pathway. The nature and severity of the abnor- 
mal sensation depend on the number, rate, timing, and 
distribution of ectopic impulses and the type and func- 
tion of nervous tissue in which they arise. Because posi- 
tive phenomena represent excessive activity in sensory 
pathways, they are not necessarily associated with a sen- 
sory deficit (loss) on examination. 



Negative phenomena represent loss of sensory func- 
tion and are characterized by diminished or absent feel- 
ing, often experienced as numbness, and by abnormal 
findings on sensory examination. In disorders affecting 
peripheral sensation, it is estimated that at least half the 
afferent axons innervating a given site are lost or func- 
tionless before a sensory deficit can be demonstrated by 
clinical examination. This threshold varies according to 
how rapidly function is lost in sensory nerve fibers. If the 
rate of loss is slow, lack of cutaneous feeling may be 
unnoticed by the patient and difficult to demonstrate on 
examination, even though few sensory fibers are func- 
tioning; if rapid, both positive and negative phenomena 
are usually conspicuous. Subclinical degrees of sensory 
dysfunction may be revealed by sensory nerve conduction 
studies or somatosensory evoked potentials (Chap. 3) . 

Whereas sensory symptoms may be either positive or 
negative, sensory signs on examination are always a mea- 
sure of negative phenomena. 

TERMINOLOGY 

Words used to characterize sensory disturbance are 
descriptive and based on convention. Paresthesias and 
dysesthesias are general terms used to denote positive sen- 
sory symptoms. The term paresthesias typically refers to 
tingling or pins-and-needles sensations but may include a 
wide variety of other abnormal sensations, except pain; it 
sometimes implies that the abnormal sensations are per- 
ceived spontaneously. The more general term dysesthesias 



116 



denotes all types of abnormal sensations, including painful 
ones, regardless of whether a stimulus is evident. 

Another set of terms refers to sensory abnormalities 
found on examination. Hypesthesia or hypoesthesia refers to 
a reduction of cutaneous sensation to a specific type of 
testing such as pressure, light touch, and warm or cold 
stimuli; anesthesia, to a complete absence of skin sensation 
to the same stimuli plus pinprick; and hypalgesia or analge- 
sia to reduced or absent pain perception (nociception), 
such as perception of the pricking quality elicited by a 
pin. Hyperesthesia means pain or increased sensitivity in 
response to touch. Similarly, allodynia describes the situa- 
tion in which a nonpainful stimulus, once perceived, is 
experienced as painful, even excruciating. An example is 
elicitation of a painful sensation by application of a vibrat- 
ing tuning fork. Hyperalgesia denotes severe pain in 
response to a mildly noxious stimulus, and hyperpathia, a 
broad term, encompasses all the phenomena described by 
hyperesthesia, allodynia, and hyperalgesia. With hyper- 
pathia, the threshold for a sensory stimulus is increased 
and perception is delayed, but once felt, is unduly painful. 

Disorders of deep sensation, arising from muscle spin- 
dles, tendons, and joints, affect proprioception (position 
sense). Manifestations include imbalance (particularly 
with eyes closed or in the dark), clumsiness of precision 
movements, and unsteadiness of gait, which are referred 
to collectively as sensory ataxia. Other findings on exami- 
nation usually, but not invariably, include reduced or 
absent joint position and vibratory sensibility and absent 
deep tendon reflexes in the affected limbs. Romberg's 
sign is positive, which means that the patient sways 
markedly or topples when asked to stand with feet close 
together and eyes closed. In severe states of deafferenta- 
tion involving deep sensation, the patient cannot walk or 
stand unaided or even sit unsupported. Continuous invol- 
untary movements (pseudoathetosis) of the outstretched 
hands and fingers occur, particularly with eyes closed. 

ANATOMY OF SENSATION 

Cutaneous afferent innervation is conveyed by a rich variety 
of receptors, both naked nerve endings (nociceptors and 
thermoreceptors) and encapsulated terminals (mechanore- 
ceptors) . Each type of receptor has its own set of sensitivities 
to specific stimuli, size and distinctness of receptive fields, 
and adaptational qualities. Much of the knowledge about 
these receptors has come from the development of tech- 
niques to study single intact nerve fibers intraneuraUy in 
awake, unanesthetized human subjects. It is possible not only 
to record from but also to stimulate single fibers in isolation. 
A single impulse, whether elicited by a natural stimulus or 
evoked by electrical microstimulation in a large myelinated 
afferent fiber may be both perceived and localized. 

Afferent fibers of all sizes in peripheral nerve trunks 
traverse the dorsal roots and enter the dorsal horn of the 



spinal cord (Fig. 12-1). From there the smaller fibers 117 
take a different route to the parietal cortex than the 
larger fibers. The polysynaptic projections of the smaller 
fibers (unmyelinated and small myelinated), which sub- 
serve mainly nociception, temperature sensibility, and 
touch, cross and ascend in the opposite anterior and lat- 
eral columns of the spinal cord, through the brainstem, 
to the ventral posterolateral (VPL) nucleus of the thala- 
mus, and ultimately project to the postcentral gyrus of the 
parietal cortex. This is the spinothalamic pathway or antero- 
lateral system. The larger fibers, which subserve tactile and 
position sense and kinesthesia, project rostrally in the 
posterior column on the same side of the spinal cord 




PONS 

Medial lemniscus 



MEDULLA 
Spinothalamic tract 



SPINAL CORD 
Spinothalamic tract 



FIGURE1 2-1 

The main somatosensory pathways. The spinothalamic tract 
(pain, thermal sense) and the posterior column-lemniscal sys- 
tem (touch, pressure, joint position) are shown. Offshoots from 
the ascending anterolateral fasciculus (spinothalamic tract) to 
nuclei in the medulla, pons, and mesencephalon and nuclear 
terminations of the tract are indicated. (From AH Ropper, RH 
Brown, in Adams and Victor's Principles of Neurology, 8th ed. 
New York, McGraw-Hill, 2007.) 






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and make their first synapse in the gracile or cuneate 
nucleus of the lower medulla. Axons of the second- 
order neuron decussate and ascend in the medial lem- 
niscus located medially in the medulla and in the 
tegmentum of the pons and midbrain and synapse in the 
VPL nucleus; the third-order neurons project to parietal 
cortex. This large-fiber system is referred to as the poste- 
rior column— medial lemniscal pathway (lemniscal, for short) . 
Note that although the lemniscal and the anterolateral 
pathways both project up the spinal cord to the thala- 
mus, it is the (crossed) anterolateral pathway that is 
referred to as the spinothalamic tract, by convention. 

Although the fiber types and functions that make up 
the spinothalamic and lemniscal systems are relatively 
well known, many other fibers, particularly those associ- 
ated with touch, pressure, and position sense, ascend in a 
diffusely distributed pattern both ipsilaterally and con- 
tralaterally in the anterolateral quadrants of the spinal 
cord. This explains why a complete lesion of the poste- 
rior columns of the spinal cord may be associated with 
little sensory deficit on examination. 



° EXAMINATION OF SENSATION 



The main components of the sensory examination are 
tests of primary sensation (pain, touch, vibration, joint 
position, and thermal sensation; Table 12-1). 

Some general principles pertain. The examiner must 
depend on patient responses, particularly when testing 
cutaneous sensation (pin, touch, warm, or cold), which 
complicates interpretation. Further, examination may be 
limited in some patients. In a stuporous patient, for exam- 
ple, sensory examination is reduced to observing the brisk- 
ness of withdrawal in response to a pinch or other noxious 
stimulus. Comparison of response on one side of the body 
to the other is essential. In the alert but uncooperative 
patient, it may not be possible to examine cutaneous 



sensation, but some idea of proprioceptive function may 
be gained by noting the patient's best performance of 
movements requiring balance and precision. Frequently, 
patients present with sensory symptoms that do not fit an 
anatomic localization and that are accompanied by either 
no abnormalities or gross inconsistencies on examination. 
The examiner should then consider whether the sensory 
symptoms are a disguised request for help with psycholog- 
ical or situational problems. Discretion must be used in 
pursuing this possibility. Finally, sensory examination of a 
patient who has no neurologic complaints can be brief 
and consist of pinprick, touch, and vibration testing in the 
hands and feet plus evaluation of stance and gait, including 
the Romberg maneuver. Evaluation of stance and gait also 
tests the integrity of motor and cerebellar systems. 

Primary Sensation 

(See Table 12-1) The sense of pain is usually tested with 
a clean pin, asking the patient to focus on the pricking 
or unpleasant quality of the stimulus and not just the 
pressure or touch sensation elicited. Areas of hypalgesia 
should be mapped by proceeding radially from the most 
hypalgesic site (Figs. 12-2 and 12-3). 

Temperature sensation, to both hot and cold, is best 
tested with small containers filled with -water of the 
desired temperature. This is impractical in most settings. 
An alternative way to test cold sensation is to touch a 
metal object, such as a tuning fork at room temperature, 
to the skin. For testing warm temperatures, the tuning 
fork or other metal object may be held under warm 
water of the desired temperature and then used. The 
appreciation of both cold and warmth should be tested 
because different receptors respond to each. 

Touch is usually tested with a -wisp of cotton or a fine 
camelhair brush. In general, it is better to avoid testing 
touch on hairy skin because of the profusion of sensory 
endings that surround each hair follicle. 



TABLE 12-1 



TESTING PRIMARY SENSATION 



SENSE 



TEST DEVICE 



ENDINGS ACTIVATED 



FIBER SIZE 
MEDIATING 



CENTRAL PATHWAY 



Pain 




Pinprick 


Cutaneous nociceptors 


Small 


SpTh, also D 


Temperature, 


heat 


Warm metal object 


Cutaneous thermoreceptors for hot 


Small 


SpTh 


Temperature, 


cold 


Cold metal object 


Cutaneous thermoreceptors for cold 


Small 


SpTh 


Touch 




Cotton wisp, 


Cutaneous mechanoreceptors, 


Large and 


Lem, also D and SpTh 






fine brush 


also naked endings 


small 




Vibration 




Tuning fork, 128 Hz 


Mechanoreceptors, especially 
pacinian corpuscles 


Large 


Lem, also D 


Joint position 




Passive movement 
of specific joints 


Joint capsule and tendon endings, 
muscle spindles 


Large 


Lem, also D 



Note: D, diffuse ascending projections in ipsilateral and contralateral anterolateral columns; SpTh, spinothalamic projection, contralateral; Lem, 
posterior column and lemniscal projection, ipsilateral. 



Ophthalmic n. 
Greater auricular n. 
Maxillary n. 
Mandibular n. 
Great auricular n. 

Transverse colli n. 
Supraclavicular nn. 

Intercostal nn. 

1. Ant cutaneous rami 

2. Lat cutaneous rami 

— Axillary n. 

Med. brachial cutaneous 
and intercostobrachial nn. 

Med. antebrachial 
cutaneous n. 




Lat. antebrachial 
cutaneous n. 



Radial n. 
Median n. 
Ulnar n. 
Iliohypogastric n. 
ioinguinal n. 
Genitofemoral n. 
Lat femoral cutaneous n. 
Obturator n. 

Ant femoral cutaneous n. 
Saphenous n. 

Lat. sural cutaneous n. 

Superficial peroneal n. 
Sural n. 

-Medial plantar n. 
Deep peroneal n. 
FIGURE 12-2 

Anterior view of dermatomes (left) and cutaneous areas 
(right) supplied by individual peripheral nerves. (Modified 
from MB Carpenter and J Sutin, in Human Neuroanatomy, 
8th ed. Baltimore, Williams & Wilkins, 1983.) 




Greater occipital n. 

Lesser occipital n. 
Greater auricular n. 
Transverse colli n. 

Cutaneous branches of 
dorsal rami of spinal nn. 

Supraclavicular n. 
Lat. cutaneous branches 
of intercostal n. 
— Axillary n. 
Post, brachial cutaneous n. 
Med. brachial cutaneous 
and intercostobrachial nn. 
Post, antebrachial 
cutaneous n. 
Lat. antebrachial 
cutaneous n. 
Med antebrachial 
cutaneous n. 
Radial n. 
Ulnar n. 
Median n. 
Iliohypogastric n. 
Cluneal nn. 
Obturator n. 
Ant. femoral cutaneous n. 



Lat. femoral cutaneous n. 

Post, femoral cutaneous n. 
Lat. sural cutaneous n. 
Sural n. 
Saphenous n. 

Calcaneal nn. 
Saphenous n. 
Plantar branches of tibial n. 



119 



FIGURE 12-3 

Posterior view of dermatomes (left) and cutaneous areas 
(right) supplied by individual peripheral nerves. (Modified 
from MB Carpenter and J Sutin, in Human Neuroanatomy, 
8th ed. Baltimore, Williams & Wilkins, 1983.) 



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Joint position testing is a measure of proprioception, 
one of the most important functions of the sensory sys- 
tem. With the patient's eyes closed, joint position is tested 
in the distal interphalangeal joint of the great toe and fin- 
gers. If errors are made in recognizing the direction of 
passive movements, more proximal joints are tested. A test 
of proximal joint position sense, primarily at the shoulder, 
is performed by asking the patient to bring the two index 
fingers together with arms extended and eyes closed. 
Normal individuals can do this accurately, with errors of 
1 cm or less. 

The sense of vibration is tested with a tuning fork 
that vibrates at 128 Hz. Vibration is usually tested over 
bony points, beginning distally; in the feet, it is tested 
over the dorsal surface of the distal phalanx of the big 
toes and at the malleoli of the ankles, and in the hands 
dorsally at the distal phalanx of the fingers. If abnormali- 
ties are found, more proximal sites can be examined. 



Vibratory thresholds at the same site in the patient and 
the examiner may be compared for control purposes. 

Quantitative Sensory Testing 

Effective sensory testing devices are now available com- 
mercially. Quantitative sensory testing is particularly use- 
ful for serial evaluation of cutaneous sensation in clinical 
trials. Threshold testing for touch and vibratory and 
thermal sensation is the most widely used application. 

Cortical Sensation 

The most commonly used tests of cortical function are 
two-point discrimination, touch localization, and bilat- 
eral simultaneous stimulation and tests for graphesthesia 
and stereognosis. Abnormalities of these sensory tests, in 
the presence of normal primary sensation in an alert 



120 



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cooperative patient, signify a lesion of the parietal cortex 
or thalamocortical projections to the parietal lobe. If 
primary sensation is altered, these cortical discriminative 
functions will usually be abnormal also. Comparisons 
should always be made between analogous sites on the 
two sides of the body because the deficit with a specific 
parietal lesion is likely to be unilateral. Interside com- 
parisons are important for all cortical sensory testing. 

Two-point discrimination is tested by special calipers, the 
points of which may be set from 2 mm to several cen- 
timeters apart and then applied simultaneously to the 
site to be tested. The pulp of the fingertips is a common 
site to test; a normal individual can distinguish about 
3-mm separation of points there. 

Touch localization is performed by light pressure for an 
instant with the examiner's fingertip or a wisp of cotton- 
wool; the patient, whose eyes are closed, is required to 
identify the site of touch with the fingertip. Bilateral simul- 
taneous stimulation at analogous sites (e.g., the dorsum of 
both hands) can be carried out to determine whether the 
perception of touch is extinguished consistently on one 
side or the other. The phenomenon is referred to as 
extinction. Graphesthesia means the capacity to recognize 
with eyes closed letters or numbers drawn by the exam- 
iner's fingertip on the palm of the hand. Once again, 
interside comparison is of prime importance. Inability to 
recognize numbers or letters is termed agraphesthesia. 

Stereognosis refers to the ability to identify common 
objects by palpation, recognizing their shape, texture, 
and size. Common standard objects, such as a key, paper 
clip, or coins, are best used. Patients with normal stere- 
ognosis should be able to distinguish a dime from a 
penny and a nickel from a quarter without looking. 
Patients should only be allowed to feel the object with 
one hand at a time. If they are unable to identify it in 
one hand, it should be placed in the other for compari- 
son. Individuals unable to identify common objects and 
coins in one hand and who can do so in the other are 
said to have astereognosis of the abnormal hand. 



LOCALIZATION OF SENSORY 
ABNORMALITIES 

Sensory symptoms and signs can result from lesions at 
almost any level of the nervous system from parietal 
cortex to the peripheral sensory receptor. Noting the 
distribution and nature of sensory symptoms and signs is 
the most important way to localize their source. Their 
extent, configuration, symmetry, quality, and severity are 
the key observations. 

Dysesthesias without sensory findings by examina- 
tion may be difficult to interpret. To illustrate, tingling 
dysesthesias in an acral distribution (hands and feet) can 
be systemic in origin, e.g., secondary to hyperventilation, 
or induced by a medication such as acetazolamide. Distal 



dysesthesias can also be an early event in an evolving 
polyneuropathy or may herald a myelopathy, such as from 
vitamin B 12 deficiency. Sometimes distal dysesthesias have 
no definable basis. In contrast, dysesthesias that corre- 
spond to a particular peripheral nerve territory denote a 
lesion of that nerve trunk. For instance, dysesthesias 
restricted to the fifth digit and the adjacent one-half of 
the fourth finger on one hand reliably point to disorder 
of the ulnar nerve, most commonly at the elbow. 

Nerve and Root 

In focal nerve trunk lesions severe enough to cause a 
deficit, sensory abnormalities are readily mapped and gen- 
erally have discrete boundaries (Figs. 12-2 and 12-3). 
Root ("radicular") lesions are frequently accompanied by 
deep, aching pain along the course of the related nerve 
trunk. With compression of a fifth lumbar (L5) or first 
sacral (SI) root, as from a ruptured intervertebral disc, sci- 
atica (radicular pain relating to the sciatic nerve trunk) is a 
frequent manifestation (Chap. 7). With a lesion affecting a 
single root, sensory deficits may be minimal or absent 
because adjacent root territories overlap extensively. 

With polyneuropathies, sensory deficits are generally 
graded, distal, and symmetric in distribution (Chap. 40). 
Dysesthesias, followed by numbness, begin in the toes 
and ascend symmetrically. When dysesthesias reach the 
knees, they have usually also appeared in the fingertips. 
The process appears to be nerve length— dependent, and 
the deficit is often described as "stocking-glove" in type. 
Involvement of both hands and feet also occurs with 
lesions of the upper cervical cord or the brainstem, but 
an upper level of the sensory disturbance may then be 
found on the trunk and other evidence of a central 
lesion may be present, such as sphincter involvement or 
signs of an upper motor neuron lesion (Chap. 10). 
Although most polyneuropathies are pansensory and 
affect all modalities of sensation, selective sensory dys- 
function according to nerve fiber size may occur. Small- 
fiber polyneuropathies are characterized by burning, 
painful dysesthesias with reduced pinprick and thermal 
sensation but sparing of proprioception, motor function, 
and deep tendon reflexes. Touch is involved variably; 
when spared, the sensory pattern is referred to as exhibit- 
ing sensory dissociation. Sensory dissociation may occur 
with spinal cord lesions as well as small-fiber neu- 
ropathies. Large-fiber polyneuropathies are characterized 
by vibration and position sense deficits, imbalance, absent 
tendon reflexes, and variable motor dysfunction but 
preservation of most cutaneous sensation. Dysesthesias, if 
present at all, tend to be tingling or bandlike in quality. 

Spinal Cord 

(See Chap. 30) If the spinal cord is transected, all sensation 
is lost below the level of transection. Bladder and bowel 



function are also lost, as is motor function. Hemisection 
of the spinal cord produces the Brown-Sequard syn- 
drome, with absent pain and temperature sensation con- 
tralaterally and loss of proprioceptive sensation and power 
ipsilaterally below the lesion (see Figs. 12-1 and 30-1). 

Numbness or paresthesias in both feet may arise from a 
spinal cord lesion; this is especially likely when the upper 
level of the sensory loss extends to the trunk. When all 
extremities are affected, the lesion is probably in the cer- 
vical region or brainstem unless a peripheral neuropathy 
is responsible. The presence of upper motor neuron signs 
(Chap. 10) supports a central lesion; a hyperesthetic band 
on the trunk may suggest the level of involvement. 

A dissociated sensory loss can reflect spinothalamic 
tract involvement in the spinal cord, especially if the 
deficit is unilateral and has an upper level on the torso. 
Bilateral spinothalamic tract involvement occurs with 
lesions affecting the center of the spinal cord, such as in 
syringomyelia. There is a dissociated sensory loss with 
impairment of pinprick and temperature appreciation 
but relative preservation of light touch, position sense, 
and vibration appreciation. 

Dysfunction of the posterior columns in the spinal 
cord or of the posterior root entry zone may lead to a 
bandlike sensation around the trunk or a feeling of tight 
pressure in one or more limbs. Flexion of the neck 
sometimes leads to an electric shock— like sensation that 
radiates down the back and into the legs (Lhermitte's 
sign) in patients with a cervical lesion affecting the pos- 
terior columns, such as from multiple sclerosis, cervical 
spondylosis, or recent irradiation to the cervical region. 

Brainstem 

Crossed patterns of sensory disturbance, in which one side 
of the face and the opposite side of the body are affected, 
localize to the lateral medulla. Here a small lesion may 
damage both the ipsilateral descending trigeminal tract 
and ascending spinothalamic fibers subserving the oppo- 
site arm, leg, and hemitorso (see Lateral medullary syn- 
drome in Fig. 21-10). A lesion in the tegmentum of the 
pons and midbrain, where the lemniscal and spinothalamic 
tracts merge, causes pansensory loss contralaterally 



Thalamus 121 

Hemisensory disturbance with tingling numbness from 
head to foot is often thalamic in origin but can also arise 
from the anterior parietal region. If abrupt in onset, the 
lesion is likely to be due to a small stroke (lacunar 
infarction), particularly if localized to the thalamus. 
Occasionally, with lesions affecting the VPL nucleus or 
adjacent white matter, a syndrome of thalamic pain, also 
called Dejerine-Roussy syndrome, may ensue. The persis- 
tent, unrelenting unilateral pain is often described in 
dramatic terms. 



Cortex 

With lesions of the parietal lobe involving either the 
cortex or subjacent white matter, the most prominent 
symptoms are contralateral hemineglect, hemi-inatten- 
tion, and a tendency not to use the affected hand and 
arm. On cortical sensory testing (e.g., two-point dis- 
crimination, graphesthesia), abnormalities are often 
found but primary sensation is usually intact. Anterior 
parietal infarction may present as a pseudothalamic syn- 
drome with contralateral loss of primary sensation from 
head to toe. Dysesthesias or a sense of numbness may 
also occur, and rarely, a painful state. 



Focal Sensory Seizures 

These are generally due to lesions in the area of the 
postcentral or precentral gyrus. The principal symptom 
of focal sensory seizures is tingling, but additional, more 
complex sensations may occur, such as a rushing feeling, 
a sense of warmth, or a sense of movement without 
detectable motion. Symptoms typically are unilateral; 
commonly begin in the arm or hand, face, or foot; and 
often spread in a manner that reflects the cortical repre- 
sentation of different bodily parts, as in a Jacksonian 
march. Duration of seizures is variable; they may be 
transient, lasting only for seconds, or persist for an hour 
or more. Focal motor features may supervene, often 
becoming generalized with loss of consciousness and 
tonic-clonic jerking. 



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Scott Andrew Josephson 



Bruce L. Miller 



Clinical Features of Delirium 1 22 

Risk Factors 1 23 

Epidemiology 1 23 

Pathogenesis 1 23 

Prevention 1 29 

Further Readings 1 29 



Confusion, a mental and behavioral state of reduced 
comprehension, coherence, and capacity to reason, is 
one of the most common problems encountered in 
medicine, accounting for a large number of emergency 
department visits, hospital admissions, and inpatient con- 
sultations. Delirium, a term used to describe an acute 
confusional state, remains a major cause of morbidity 
and mortality, contributing billions of dollars yearly to 
health care costs in the United States alone. Delirium 
often goes unrecognized despite clear evidence that it is 
usually the cognitive manifestation of serious underlying 
medical or neurologic illness. 

CLINICAL FEATURES OF DELIRIUM 

A multitude of terms are used to describe delirium, 
including encephalopathy, acute brain failure, acute con- 
fusional state, and postoperative or intensive care unit 
(ICU) psychosis. Delirium has many clinical manifesta- 
tions, but essentially it is defined as a relatively acute 
decline in cognition that fluctuates over hours or days. 
The hallmark of delirium is a deficit of attention, 
although all cognitive domains — including memory, 
executive function, visuospatial tasks, and language — are 
variably involved. Associated symptoms may include 
altered sleep-wake cycles, perceptual disturbances such 
as hallucinations or delusions, affect changes, and auto- 
nomic findings including heart rate and blood pressure 
instability. 



Delirium is a clinical diagnosis that can only be made 
at the bedside. Two broad clinical categories of delirium 
have been described, hyperactive and hypoactive sub- 
types, based on differential psychomotor features. The 
cognitive syndrome associated with severe alcohol with- 
drawal remains the classic example of the hyperactive 
subtype, featuring prominent hallucinations, agitation, 
and hyperarousal, often accompanied by life -threatening 
autonomic instability. In striking contrast is the hypoac- 
tive subtype of delirium, exemplified by opiate intoxica- 
tion, in which patients are withdrawn and quiet, with 
prominent apathy and psychomotor slowing. 

This dichotomy between subtypes of delirium is a 
useful construct, but patients often fall somewhere along 
a spectrum between the hyperactive and hypoactive 
extremes, sometimes fluctuating from one to the other 
within minutes. Therefore, clinicians must recognize the 
broad range of presentations of delirium in order to 
identify all patients with this potentially reversible cog- 
nitive disturbance. Hyperactive patients, such as those 
with delirium tremens, are easily recognized by their 
characteristic severe agitation, tremor, hallucinations, and 
autonomic instability. Patients who are quietly disturbed 
are more often overlooked on the medical wards and in 
the ICU, yet multiple studies suggest that this under- 
recognized hypoactive subtype is associated with worse 
outcomes. 

The reversibility of delirium is emphasized because 
many etiologies, such as systemic infection and medication 



122 



effects, can be easily treated. However, the long-term 
cognitive effects of delirium remain largely unknown and 
understudied. Some episodes of delirium continue for 
weeks, months, or even years. The persistence of delir- 
ium in some patients and its high recurrence rate may 
be due to inadequate treatment of the underlying etiol- 
ogy for the syndrome. In some instances, delirium does 
not disappear because there is underlying permanent 
neuronal damage. Even after an episode of delirium 
resolves, there may still be lingering effects of the disor- 
der. A patient's recall of events after delirium varies 
widely, ranging from complete amnesia to repeated 
reexperiencing of the frightening period of confusion in 
a disturbing manner, similar to what is seen in patients 
with posttraumatic stress disorder. 

RISK FACTORS 

An effective primary prevention strategy for delirium 
begins with identification of patients at highest risk, includ- 
ing those preparing for elective surgery or being admitted 
to the hospital. Although no single validated scoring system 
has been widely accepted as a screen for asymptomatic 
patients, there are multiple well-established risk factors for 
delirium. 

The two most consistently identified risks are older age 
and baseline cognitive dysfunction. Individuals who are 
older than 65 years or exhibit low scores on standardized 
tests of cognition develop delirium upon hospitalization at 
a rate approaching 50%. Whether age and baseline cogni- 
tive dysfunction are truly independent risk factors is 
uncertain. Other predisposing factors include sensory 
deprivation, such as preexisting hearing and visual impair- 
ment, as well as indices for poor overall health, including 
baseline immobility, malnutrition, and underlying medical 
or neurologic illness. 

In-hospital risks for delirium include the use of blad- 
der catheterization, physical restraints, sleep and sensory 
deprivation, and the addition of three or more new 
medications. Avoiding such risks remains a key compo- 
nent of delirium prevention as well as treatment. Surgi- 
cal and anesthetic risk factors for the development of 
postoperative delirium include specific procedures such 
as those involving cardiopulmonary bypass and inade- 
quate or excessive treatment of pain in the immediate 
postoperative period. 

The relationship between delirium and dementia 
(Chap. 23) is complicated by significant overlap between 
these two conditions, and it is not always simple to dis- 
tinguish between the two. Dementia and preexisting 
cognitive dysfunction serve as major risk factors for 
delirium, and at least two-thirds of cases of delirium 
occur in patients with coexisting underlying dementia. 
A form of dementia with parkinsonism, termed dementia 
with Lewy bodies, is characterized by a fluctuating course, 



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prominent visual hallucinations, parkinsonism, and an 123 
attentional deficit that clinically resembles hyperactive 
delirium. Delirium in the elderly often reflects an insult 
to the brain that is vulnerable due to an underlying 
neurodegenerative condition. Therefore, the develop- 
ment of delirium sometimes heralds the onset of a pre- 
viously unrecognized brain disorder. 



EPIDEMIOLOGY 

Delirium is a common disease, but its reported inci- 
dence has varied widely based on the criteria used to 
define the disorder. Estimates of delirium in hospitalized 
patients range from 14 to 56%, with higher rates 
reported for elderly patients and patients undergoing hip 
surgery. Older patients in the ICU have especially high 
rates of delirium ranging from 70 to 87%. The condition 
is not recognized in up to one-third of delirious inpa- 
tients, and the diagnosis is especially problematic in the 
ICU environment where cognitive dysfunction is often 
difficult to appreciate in the setting of serious systemic 
illness and sedation. Delirium in the ICU should be 
viewed as an important manifestation of organ dysfunc- 
tion not unlike liver, kidney, or heart failure. Outside 
of the acute hospital setting, delirium occurs in nearly 
two-thirds of patients in nursing homes and in over 80% 
of those at the end of life. These estimates emphasize the 
remarkably high frequency of this cognitive syndrome in 
older patients, a population expected to grow in the 
upcoming decade with the aging of the "baby boom" 
generation. 

In previous decades an episode of delirium was viewed 
as a transient condition that carried a benign prognosis. 
Delirium has now been clearly associated with substan- 
tial morbidity and increased mortality, and is increasingly 
recognized as a sign of serious underlying illness. Recent 
estimates of in-hospital mortality among delirious patients 
have ranged from 25—33%, a rate that is similar to patients 
with sepsis. Patients with an in-hospital episode of delir- 
ium have a higher mortality in the months and years 
following their illness compared with age-matched non- 
delirious hospitalized patients. Delirious hospitalized 
patients have a longer length of stay, are more likely to 
be discharged to a nursing home, and are more likely to 
experience subsequent episodes of delirium; as a result, 
this condition has enormous economic implications. 



PATHOGENESIS 

The pathogenesis and anatomy of delirium are incom- 
pletely understood. The attentional deficit that serves as 
the neuropsychological hallmark of delirium appears to 
have a diffuse localization with the brainstem, thalamus, 
prefrontal cortex, thalamus, and parietal lobes. Rarely, 



124 



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focal lesions such as ischemic strokes have led to delir- 
ium in otherwise healthy persons; right parietal and 
medial dorsal thalamic lesions have been reported most 
commonly, stressing the relevance of these areas to delir- 
ium pathogenesis. In most cases, delirium results from 
widespread disturbances in cortical and subcortical 
regions, rather than a focal neuroanatomic cause. Elec- 
troencephalogram (EEG) data in persons with delirium 
usually show symmetric slowing, a nonspecific finding 
supporting diffuse cerebral dysfunction. 

Deficiency of acetylcholine often plays a key role in 
delirium pathogenesis. Medications with anticholinergic 
properties can precipitate delirium in susceptible indi- 
viduals, and therapies designed to boost cholinergic tone 
such as cholinesterase inhibitors have, in small trials, 
been shown to relieve symptoms of delirium. Dementia 
patients are susceptible to episodes of delirium, and 
those -with Alzheimer's pathology are known to have a 
chronic cholinergic deficiency state due to degeneration 
of acetylcholine-producing neurons in the basal fore- 
brain. Another common dementia associated with 
decreased acetylcholine levels, dementia with Lewy bod- 
ies, clinically mimics delirium in some patients. Other 
neurotransmitters are also likely involved in this diffuse 
cerebral disorder. For example, increases in dopamine 
can also lead to delirium. Patients with Parkinson's dis- 
ease treated with dopaminergic medications can develop 
a delirious-like state that features visual hallucinations, 
fluctuations, and confusion. In contrast, reducing dopamin- 
ergic tone with dopamine antagonists such as typical and 
atypical antipsychotic medications has long been recog- 
nized as effective symptomatic treatment in patients with 
delirium. 

Not all individuals exposed to the same insult will 
develop signs of delirium. A low dose of an anticholin- 
ergic medication may have no cognitive effects on a 
healthy young adult but may produce a florid delirium 
in an elderly person with known underlying dementia. 
However, an extremely high dose of the same anti- 
cholinergic medication may lead to delirium even in 
healthy young persons. This concept of delirium devel- 
oping as the result of an insult in predisposed individu- 
als is currently the most widely accepted pathogenic 
construct. Therefore, if a previously healthy individual 
with no known history of cognitive illness develops 
delirium in the setting of a relatively minor insult such 
as elective surgery or hospitalization, then an unrecog- 
nized underlying neurologic illness such as a neurode- 
generative disease, multiple previous strokes, or another 
diffuse cerebral cause should be considered. In this con- 
text, delirium can be viewed as the symptom resulting 
from a "stress test for the brain" induced by the insult. 
Exposure to known inciting factors such as systemic 
infection or offending drugs can unmask a decreased cere- 
bral reserve and herald a serious underlying and poten- 
tially treatable illness. 



Approach to the Patient: 

DELIRIUM 



As the diagnosis of delirium is clinical and made at 
the bedside, a careful history and physical examina- 
tion is necessary -when evaluating patients with possi- 
ble confusional states. Screening tools can aid physi- 
cians and nurses in identifying patients -with delirium, 
including the Confusion Assessment Method (CAM) 
(Table 13-1); the Organic Brain Syndrome Scale; the 
Delirium Rating Scale; and, in the ICU, the Delirium 
Detection Score and the ICU version of the CAM. 
These scales are based on criteria from the American 
Psychiatric Association's Diagnostic and Statistical Man- 
ual of Mental Disorders (DSM) or the World Health 
Organization's International Classification of Diseases 
(ICD). Unfortunately, these scales themselves do not 
identify the full spectrum of patients with delirium. 
All patients who are acutely confused should be pre- 
sumed delirious regardless of their presentation due 
to the wide variety of possible clinical features. A course 



TABLE 13-1 



THE CONFUSION ASSESSMENT METHOD (CAM) 
DIAGNOSTIC ALGORITHM 



The diagnosis of delirium requires the presence of 
features 1 and 2 and of either 3 or 4. a 
Feature 1 : Acute onset and fluctuating course 
This feature is satisfied by positive responses to 
these questions: Is there evidence of an acute 
change in mental status from the patient's baseline? 
Did the (abnormal) behavior fluctuate during the 
day — that is, tend to come and go — or did it 
increase and decrease in severity? 
Feature 2: Inattention 
This feature is satisfied by a positive response to this 
question: Did the patient have difficulty focusing 
attention — for example, was easily distractible — or 
have difficulty keeping track of what was being 
said? 
Feature 3: Disorganized thinking 
This feature is satisfied by a positive response to this 
question: Was the patient's thinking disorganized 
or incoherent, such as rambling or irrelevant 
conversation, unclear or illogical flow of ideas, or 
unpredictable switching from subject to subject? 
Feature 4: Altered level of consciousness 
This feature is satisfied by any answer other than 
"alert" to this question: Overall, how would you rate 
this patient's level of consciousness: alert (normal), 
vigilant (hyperalert), lethargic (drowsy, easily 
aroused), stupor (difficult to arouse), or coma 
(unarousable)? 

information is usually obtained from a reliable reporter, such as a 

family member, caregiver, or nurse. 

Source: Modified from Inouye SK et al: Ann Intern Med 113:941, 

1990. 



that fluctuates over hours or days and may worsen at 
night (termed sundouming) is typical but not essential 
for the diagnosis. Observation of the patient will usu- 
ally reveal an altered level of consciousness or a deficit 
of attention. Other hallmark features that may be pre- 
sent in the delirious patient include alteration of 
sleep-wake cycles, thought disturbances such as hallu- 
cinations or delusions, autonomic instability, and 
changes in affect. 



Other important elements of the history include 
screening for symptoms of organ failure or systemic 
infection, which often contributes to delirium in the 
elderly. A history of illicit drug use, alcoholism, or 
toxin exposure is common in younger delirious 
patients. Finally, asking the patient and collateral 
source about other symptoms that may accompany 
delirium, such as depression or hallucinations, may 
help identify potential therapeutic targets. 



125 



HISTORY It may be difficult to elicit an accurate 
history in delirious patients who have altered levels of 
consciousness or impaired attention. Information 
from a collateral source such as a spouse or other 
family member is therefore invaluable. The three most 
important pieces of history include the patient's base- 
line cognitive function, the time course of the present 
illness, and current medications. 

Premorbid cognitive function can be assessed 
through the collateral source or, if needed, via a 
review of outpatient records. Delirium by definition 
represents a change that is relatively acute, usually over 
hours to days, from a cognitive baseline. As a result, an 
acute confusional state is nearly impossible to diagnose 
without some knowledge of baseline cognitive func- 
tion. Without this information, many patients with 
dementia or depression may be mistaken as delirious 
during a single initial evaluation. Patients with a more 
hypoactive, apathetic presentation with psychomotor 
slowing may only be identified as being different from 
baseline through conversations with family members. 
A number of validated instruments have been shown 
to accurately diagnose cognitive dysfunction using a 
collateral source including the modified Blessed 
Dementia Rating Scale and Clinical Dementia Rating 
(CDR). Baseline cognitive impairment is common in 
patients with delirium. Even when no such history of 
cognitive impairment is elicited, there should still be a 
high suspicion for previously unrecognized underlying 
neurologic disorder. 

Establishing the time course of cognitive change is 
important not only to make a diagnosis of delirium 
but also to correlate the onset of the illness with 
potentially treatable etiologies such as recent medica- 
tion changes or symptoms of systemic infection. 

Medications remain a common cause of delirium, 
especially those compounds with anticholinergic or 
sedative properties. It is estimated that nearly one- 
third of all cases of delirium are secondary to medica- 
tions, especially in the elderly. Medication histories 
should include all prescription as well as over-the- 
counter and herbal substances taken by the patient 
and any recent changes in dosing or formulation, 
including substitution of generics for brand-name 
medications. 



PHYSICAL EXAMINATION The general physical 
examination in a delirious patient should include a 
careful screening for signs of infection such as fever, 
tachypnea, pulmonary consolidation, heart murmur, 
or stiff neck. The patient's fluid status should be 
assessed; both dehydration and fluid overload with 
resultant hypoxia have been associated with delirium, 
and each is usually easily rectified. The appearance of 
the skin can be helpful, showing jaundice in hepatic 
encephalopathy, cyanosis in hypoxia, or needle tracks 
in patients using intravenous drugs. 

The neurologic examination requires a careful 
assessment of mental status. Patients with delirium 
often present with a fluctuating course; therefore the 
diagnosis can be missed when relying on a single 
time point of evaluation. Some but not all patients 
exhibit the characteristic pattern of sundowning, a 
worsening of their condition in the evening. In these 
cases, assessment only during morning rounds may be 
falsely reassuring. 

An altered level of consciousness ranging from 
hyperarousal to lethargy to coma is present in most 
patients with delirium and can be easily assessed at 
the bedside. In the patient with a relatively normal 
level of consciousness, a screen for an attentional 
deficit is in order, as this deficit is the classic neu- 
ropsychological hallmark of delirium. Attention can 
be assessed while taking a history from the patient. 
Tangential speech, a fragmentary flow of ideas, or 
inability to follow complex commands often signifies 
an attentional problem. Formal neuropsychological 
tests to assess attention exist, but a simple bedside test 
of digit span forward is quick and fairly sensitive. In 
this task, patients are asked to repeat successively 
longer random strings of digits beginning with two 
digits in a row. Average adults can repeat a string of 
between five to seven digits before faltering; a digit 
span of four or less usually indicates an attentional 
deficit unless hearing or language barriers are present. 

More formal neuropsychological testing can be 
extraordinarily helpful in assessing the delirious 
patient, but it is usually too cumbersome and time- 
consuming in the inpatient setting. A simple Mini 
Mental Status Examination (MMSE) (Table 23-5) can 
provide some information regarding orientation, 



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language, and visuospatial skills; however, perfor- 
mance of some tasks on the MMSE such as spelling 
"world" backwards or serial subtraction of digits will 
be impaired by delirious patients' attentional deficits 
alone and are therefore unreliable. 

The remainder of the screening neurologic exami- 
nation should focus on identifying new focal neuro- 
logic deficits. Focal strokes or mass lesions in isolation 
are rarely the cause of delirium, but patients with 
underlying extensive cerebrovascular disease or neu- 
rodegenerative conditions may not be able to cogni- 
tively tolerate even relatively small new insults. 
Patients should also be screened for additional signs 
of neurodegenerative conditions such as parkinson- 
ism, which is seen not only in idiopathic Parkinson's 
disease but also in other dementing conditions such 
as Alzheimer's disease, dementia with Lewy bodies, 
and progressive supranuclear palsy. The presence of 
multifocal myoclonus or asterixis on the motor 
examination is nonspecific but usually indicates a 
metabolic or toxic etiology of the delirium. 

ETIOLOGY Some etiologies can be easily dis- 
cerned through a careful history and physical exami- 
nation, while others require confirmation -with labo- 
ratory studies, imaging, or other ancillary tests. A 
large, diverse group of insults can lead to delirium, 
and the cause in many patients is often multifactorial. 
Common etiologies are listed in Table 13-2. 

Prescribed, over-the-counter, and herbal medica- 
tions are common precipitants of delirium. Drugs 
with anticholinergic properties, narcotics, and benzo- 
diazepines are especially frequent offenders, but 
nearly any compound can lead to cognitive dysfunc- 
tion in a predisposed patient. While an elderly patient 
with baseline dementia may become delirious upon 
exposure to a relatively low dose of a medication, 
other less-susceptible individuals may only become 
delirious with very high doses of the same medica- 
tion. This observation emphasizes the importance of 
correlating the timing of recent medication changes, 
including dose and formulation, with the onset of 
cognitive dysfunction. 

In younger patients especially, illicit drugs and 
toxins are common causes of delirium. In addition 
to more classic drugs of abuse, the recent rise in 
availability of so-called club drugs, such as methyl- 
enedioxymethamphetamine (MDMA, ecstasy), y- 
hydroxybutyrate (GHB), and the PCP-like agent 
ketamine, has led to an increase in delirious young 
persons presenting to acute care settings. Many com- 
mon prescription drugs such as oral narcotics and 
benzodiazepines are now often abused and readily 
available on the street. Alcohol intoxication with high 
serum levels can cause confusion, but more commonly 



TABLE 13-2 



COMMON ETIOLOGIES OF DELIRIUM 



Toxins 

Prescription medications: especially those with 
anticholinergic properties, narcotics and 
benzodiazepines 

Drugs of abuse: alcohol intoxication and alcohol 
withdrawal, opiates, ecstasy, LSD, GHB, PCP, 
ketamine, cocaine 

Poisons: inhalants, carbon monoxide, ethylene glycol, 
pesticides 
Metabolic conditions 

Electrolyte disturbances: hypoglycemia, hyperglycemia, 
hyponatremia, hypernatremia, hypercalcemia, 
hypocalcemia, hypomagnesemia 

Hypothermia and hyperthermia 

Pulmonary failure: hypoxemia and hypercarbia 

Liver failure/hepatic encephalopathy 

Renal failure/uremia 

Cardiac failure 

Vitamin deficiencies: B 12 , thiamine, folate, niacin 

Dehydration and malnutrition 

Anemia 
Infections 

Systemic infections: urinary tract infections, 
pneumonia, skin and soft tissue infections, sepsis 

CNS infections: meningitis, encephalitis, brain abscess 
Endocrinologic conditions 

Hyperthyroidism, hypothyroidism 

Hyperparathyroidism 

Adrenal insufficiency 
Cerebrovascular disorders 

Global hypoperfusion states 

Hypertensive encephalopathy 

Focal ischemic strokes and hemorrhages, especially 
nondominant parietal and thalamic lesions 
Autoimmune disorders 

CNS vasculitis 

Cerebral lupus 
Seizure-related disorders 

Nonconvulsive status epilepticus 

Intermittent seizures with prolonged post-ictal states 
Neoplastic disorders 

Diffuse metastases to the brain 

Gliomatosis cerebri 

Carcinomatous meningitis 
Hospitalization 
Terminal end of life delirium 

Note: LSD, lysergic acid diethylamide; GHB, y-hydroxybutyrate; 
PCP, phencyclidine; CNS, central nervous system. 



it is withdrawal from alcohol that leads to a classic 
hyperactive delirium. Alcohol and benzodiazepine 
withdrawal should be considered in all cases of delir- 
ium as even patients who drink only a few servings 
of alcohol every day can experience relatively severe 
withdrawal symptoms upon hospitalization. 



Metabolic abnormalities such as electrolyte distur- 
bances of sodium, calcium, magnesium, or glucose can 
cause delirium, and mild derangements can lead to 
substantial cognitive disturbances in susceptible indi- 
viduals. Other common metabolic etiologies include 
liver and renal failure, hypercarbia and hypoxia, vitamin 
deficiencies of thiamine and B 12 , autoimmune disor- 
ders including CNS vasculitis, and endocrinopathies 
such as thyroid and adrenal disorders. 

Systemic infections often cause delirium, especially 
in the elderly. A common scenario involves the devel- 
opment of an acute cognitive decline in the setting of 
a urinary tract infection in a patient with baseline 
dementia. Pneumonia, skin infections such as celluli- 
tis, and frank sepsis can also lead to delirium. This so- 
called septic encephalopathy, often seen in the ICU, is 
likely due to the release of proinflammatory cytokines 
and their diffuse cerebral effects. CNS infections such 
as meningitis, encephalitis, and abscess are less-com- 
mon etiologies of delirium; however, given the high 
mortality associated with these conditions when not 
treated quickly, clinicians must always maintain a high 
index of suspicion. 

In some susceptible individuals, exposure to the 
unfamiliar environment of a hospital can lead to delir- 
ium. This etiology usually occurs as part of a multifac- 
torial delirium and should be considered a diagnosis of 
exclusion after all other causes have been thoroughly 
investigated. Many primary prevention and treatment 
strategies for delirium involve relatively simple meth- 
ods to address those aspects of the inpatient setting that 
are most confusing. 

Cerebrovascular etiologies are usually due to global 
hypoperfusion in the setting of systemic hypotension 
from heart failure, septic shock, dehydration, or ane- 
mia. Focal strokes in the right parietal lobe and 
medial dorsal thalamus can rarely lead to a delirious 
state. A more common scenario involves a new focal 
stroke or hemorrhage causing confusion in a patient 
who has decreased cerebral reserve. In these individu- 
als, it is sometimes difficult to distinguish between 
cognitive dysfunction resulting from the new neu- 
rovascular insult itself and delirium due to the infec- 
tious, metabolic, and pharmacologic complications 
that can accompany hospitalization after stroke. 

Because a fluctuating course is often seen in delir- 
ium, intermittent seizures may be overlooked when 
considering potential etiologies. Both nonconvulsive 
status epilepticus as well as recurrent focal or general- 
ized seizures followed by post-ictal confusion can 
cause delirium; EEC remains essential for this diag- 
nosis. Seizure activity spreading from an electrical 
focus in a mass or infarct can explain global cognitive 
dysfunction caused by relatively small lesions. 



It is very common for patients to experience delir- 
ium at the end of life in palliative care settings. This 
condition, sometimes described as terminal restlessness, 
must be identified and treated aggressively as it is an 
important cause of patient and family discomfort at 
the end of life. It should be remembered that these 
patients may also be suffering from more common 
etiologies of delirium such as systemic infection. 

LABORATORY AND DIAGNOSTIC EVALUA- 
TION A cost-effective approach to the diagnostic 
evaluation of delirium allows the history and physical 
examination to guide tests. No established algorithm 
for workup 'will fit all delirious patients due to the 
staggering number of potential etiologies, but one 
step-wise approach is detailed in Table 13-3. If a 
clear precipitant is identified early, such as an offend- 
ing medication, then little further workup is required. 
If, however, no likely etiology is uncovered with ini- 
tial evaluation, an aggressive search for an underlying 
cause should be initiated. 

Basic screening labs, including a complete blood 
count, electrolyte panel, and tests of liver and renal 
function, should be obtained in all patients with delir- 
ium. In elderly patients, screening for systemic infection, 
including chest radiography, urinalysis and culture, and 
possibly blood cultures, is important. In younger indi- 
viduals, serum and urine drug and toxicology screen- 
ing may be appropriate early in the workup. Addi- 
tional laboratory tests addressing other autoimmune, 
endocrinologic, metabolic, and infectious etiologies 
should be reserved for patients in whom the diagnosis 
remains unclear after initial testing. 

Multiple studies have demonstrated that brain 
imaging in patients with delirium is often unhelpful. 
However, if the initial workup is unrevealing, most 
clinicians quickly move toward imaging of the brain 
in order to exclude structural causes. A noncontrast 
CT scan can identify large masses and hemorrhages 
but is otherwise relatively insensitive for discovering 
an etiology of delirium. The ability of MRI to iden- 
tify most acute ischemic strokes as well as to provide 
neuroanatomic detail that gives clues to possible 
infectious, inflammatory, neurodegenerative, and neo- 
plastic conditions makes it the test of choice. Since 
MRI techniques are limited by availability, speed of 
imaging, patient cooperation, and contraindications 
to magnetic exposure, many clinicians begin with CT 
scanning and proceed to MRI if the etiology of delir- 
ium remains elusive. 

Lumbar puncture (LP) must be obtained immedi- 
ately, after appropriate neuroimaging, in all patients in 
whom CNS infection is suspected. Spinal fluid exam- 
ination can also be useful in identifying inflammatory 
and neoplastic conditions as well as in the diagnosis 



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STEP-WISE EVALUATION OF A PATIENT WITH 
DELIRIUM 



Initial evaluation 
History with special attention to medications (including 

over-the-counter and herbals) 
General physical examination and neurologic 

examination 
Complete blood count 
Electrolyte panel including calcium, magnesium, 

phosphorus 

Liver function tests including albumin 
Renal function tests 
First-tier further evaluation guided by initial evaluation 
Systemic infection screen 
Urinalysis and culture 
Chest radiograph 
Blood cultures 
E I ect rocard i og ram 
Arterial blood gas 
Serum and/or urine toxicology screen (perform earlier in 

young persons) 
Brain imaging with MRI with diffusion and gadolinium 

(preferred) or CT 
Suspected CNS infection: lumbar puncture following 

brain imaging 
Suspected seizure-related etiology: electroencephalogram 

(EEG) (if high suspicion should be performed 

immediately) 
Second-tier further evaluation 
Vitamin levels: B 12 , folate, thiamine 
Endocrinologic laboratories: thyroid-stimulating 

hormone (TSH) and free T4; Cortisol 
Serum ammonia 
Sedimentation rate 
Autoimmune serologies: antinuclear antibodies (ANA), 

complement levels; p-ANCA, c-ANCA 
Infectious serologies: rapid plasmin reagin (RPR); fungal 

and viral serologies if high suspicion; HIV antibody 
Lumbar puncture (if not already performed) 
Brain MRI with and without gadolinium (if not already 

performed) 

Note: p-ANCA, perinuclear antineutrophil cytoplasmic antibody; 
c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody. 



of hepatic encephalopathy through elevated CSF glu- 
tamine levels. As a result, LP should be considered in 
any delirious patient with a negative workup. EEG 
does not have a routine role in the workup of delir- 
ium, but it remains invaluable if seizure -related eti- 
ologies are considered. 



Be 



Treatment: 
DELIRIUM 



Management of delirium begins with treatment of the 
underlying inciting factor (e.g., patients with systemic 



infections should be given appropriate antibiotics and 
underlying electrolyte disturbances judiciously cor- 
rected). These treatments often lead to prompt resolu- 
tion of delirium. Blindly targeting the symptoms of delir- 
ium pharmacologically only serves to prolong the time 
patients remain in the confused state and may mask 
important diagnostic information. Recent trials of med- 
ications used to boost cholinergic tone in delirious 
patients have led to mixed results, and this strategy is 
not currently recommended. 

Relatively simple methods of supportive care can be 
highly effective in treating patients with delirium. Reori- 
entation by the nursing staff and family combined with 
visible clocks, calendars, and outside-facing windows 
can reduce confusion. Sensory isolation should be pre- 
vented by providing glasses and hearing aids to those 
patients who need them. Sundowning can be 
addressed to a large extent through vigilance to appro- 
priate sleep-wake cycles. During the day, a well-lit room 
should be accompanied by activities or exercises to pre- 
vent napping. At night, a quiet, dark environment with 
limited interruptions by staff can assure proper rest. 
These sleep-wake cycle interventions are especially 
important in the ICU setting as the usual constant 24-h 
activity commonly provokes delirium. Attempting to 
mimic the home environment as much as possible has 
also been shown to help treat and even prevent delir- 
ium. Visits from friends and family throughout the day 
minimize the anxiety associated with the constant flow 
of new faces of staff and physicians. Allowing hospital- 
ized patients to have access to home bedding, clothing, 
and nightstand objects makes the hospital environment 
less foreign and therefore less confusing. Simple stan- 
dard nursing practices such as maintaining proper 
nutrition and volume status as well as managing incon- 
tinence and skin breakdown also help to alleviate dis- 
comfort and resulting confusion. 

In some instances, patients pose a threat to their own 
safety or to the safety of staff members, and acute man- 
agement is required. Bed alarms and personal sitters are 
more effective and much less disorienting than physical 
restraints. Chemical restraints should be avoided, but, 
when necessary, very-low-dose typical or atypical 
antipsychotic medications administered on an as- 
needed basis are effective. The recent association of 
atypical antipsychotic use in the elderly with increased 
mortality underscores the importance of using these 
medications judiciously and only as a last resort. Benzo- 
diazepines are not as effective as antipsychotics and 
often worsen confusion via their sedative properties. 
Although many clinicians still use benzodiazepines to 
treat acute confusion, their use should be limited only 
to cases in which delirium is caused by alcohol or ben- 
zodiazepine withdrawal. 



PREVENTION 

Given the high morbidity associated with delirium and 
the tremendously increased health care costs that 
accompany it, development of an effective strategy to 
prevent delirium in hospitalized patients is extremely 
important. Successful identification of high-risk patients 
is the first step, followed by initiation of appropriate 
interventions. One trial randomized more than 850 
elderly inpatients to simple standardized protocols used 
to manage risk factors for delirium, including cognitive 
impairment, immobility, visual impairment, hearing 
impairment, sleep deprivation, and dehydration. Signifi- 
cant reductions in the number and duration of episodes 
of delirium were observed in the treatment group, but 
unfortunately delirium recurrence rates were unchanged. 
Recent trials in the ICU have focused on identifying 
sedatives, such as dexmedetomidine, that are less likely 
to lead to delirium in critically ill patients. All hospitals 
and health care systems should work toward developing 



standardized protocols to address common risk factors 129 
with the goal of decreasing the incidence of delirium. 

Acknowledgment 

In the previous edition, Allan H. Ropper contributed to a sec- 
tion on acute confusional states that was incorporated into this 
current chapter. 

FURTHER READINGS 

FONG TG et al: Delirium in elderly adults: diagnosis, prevention, and 
treatment. Nat Rev Neurol 5:210, 2009 

GlRARD TD et al: Delirium in the intensive care unit. Crit Care 12 
Suppl 3:S3, 2008 

INOUYE SK et al: A multicomponent intervention to prevent delir- 
ium in hospitalized older patients. N Engl J Med 340:669, 1999 

Lat I et al: The impact of delirium on clinical outcomes in mechani- O 
cally ventilated surgical and trauma patients. Crit Care Med ^, 
37:1898,2009 5. 

RlKER RR et al: Dexmedetomidine vs midazolam for sedation of ^ 

critically ill patients: a randomized trial. JAMA 301:489, 2009 QJ 

Q. 

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CD 




Allan H. Ropper 



The Anatomy and Physiology of Coma 1 31 

Laboratory Studies and Imaging 1 36 

Differential Diagnosis of Coma 1 37 

Brain Death 1 38 

Prognosis 1 39 

Further Readings 1 39 



Coma is among the most common and striking prob- 
lems in general medicine. It accounts for a substantial 
portion of admissions to emergency departments and 
occurs on all hospital services. Because coma demands 
immediate attention, the physician must employ an orga- 
nized approach. 

There is a continuum of states of reduced alertness, 
the severest form being coma, a deep sleeplike state from 
which the patient cannot be aroused. Stupor refers to a 
higher degree of arousability in which the patient can 
be awakened only by vigorous stimuli, accompanied by 
motor behavior that leads to avoidance of uncomfort- 
able or aggravating stimuli. Drowsiness, which is familiar 
to all persons, simulates light sleep and is characterized 
by easy arousal and the persistence of alertness for brief 
periods. Drowsiness and stupor are usually attended by 
some degree of confusion (Chap. 13). A narrative descrip- 
tion of the level of arousal and of the type of responses 
evoked by various stimuli, precisely as observed at the 
bedside, is preferable to ambiguous terms such as lethargy, 
semicoma, or obtundation. 

Several other neurologic conditions render patients 
apparently unresponsive and thereby simulate coma, and 
certain subsyndromes of coma must be considered sepa- 
rately because of their special significance. Among the 
latter, the vegetative state signifies an awake but nonre- 
sponsive state. These patients have emerged from coma 
after a period of days or weeks to a state in which the 
eyelids are open, giving the appearance of wakefulness. 



Yawning, coughing, swallowing, as well as limb and head 
movements persist, but there are few, if any, meaningful 
responses to the external and internal environment — in 
essence, an "awake coma." Respiratory and autonomic 
functions are retained. The term "vegetative" is unfortu- 
nate as it is subject to misinterpretation by laypersons. 
The possibility of incorrectly attributing meaningful 
behavior to these patients has created inordinate prob- 
lems. There are always accompanying signs that indicate 
extensive damage in both cerebral hemispheres, e.g., 
decerebrate or decorticate limb posturing and absent 
responses to visual stimuli (see later). In the closely 
related but less severe minimally conscious state the patient 
may make intermittent rudimentary vocal or motor 
responses. Cardiac arrest with cerebral hypoperfusion and 
head injuries are the most common causes of the vegeta- 
tive and minimally conscious states (Chaps. 22 and 31). 
The prognosis for regaining mental faculties once the 
vegetative state has supervened for several months is very 
poor, and after a year, almost nil, hence the term persistent 
vegetative state. Most reports of dramatic recovery, when 
investigated carefully, are found to yield to the usual rules 
for prognosis, but there have been rare instances in which 
recovery has occurred to a demented condition and, in 
rare childhood cases, to an even better state. 

Quite apart from the above conditions, certain syn- 
dromes that affect alertness are prone to be misinterpreted 
as stupor or coma. Akinetic mutism refers to a partially or 
fully awake state in which the patient is able to form 



130 



impressions and think but remains virtually immobile and 
mute. The condition results from damage in the regions 
of the medial thalamic nuclei or the frontal lobes (partic- 
ularly lesions situated deeply or on the orbitofrontal sur- 
faces), or from hydrocephalus. The term abulia is in 
essence a milder form of akinetic mutism, used to 
describe mental and physical slowness and diminished 
ability to initiate activity. It is also generally the result of 
damage to the frontal lobe network (Chap. 15). Catatonia 
is a curious hypomobile and mute syndrome that arises as 
part of a major psychosis, usually schizophrenia or major 
depression. Catatonic patients make few voluntary or 
responsive movements, although they blink, swallow, and 
may not appear distressed. There are nonetheless signs that 
the patient is responsive, although it may take some inge- 
nuity on the part of the examiner to demonstrate them. 
For example, eyelid elevation is actively resisted, blinking 
occurs in response to a visual threat, and the eyes move 
concomitantly with head rotation, all of which are incon- 
sistent with the presence of a brain lesion. It is character- 
istic but not invariable in catatonia for the limbs to retain 
the postures in which they have been placed by the 
examiner ("waxy flexibility," or catalepsy). Upon recovery, 
such patients have some memory of events that occurred 
during their catatonic stupor. The appearance is superfi- 
cially similar to akinetic mutism, but clinical evidence of 
cerebral damage such as Babinski signs and hypertonicity 
of the limbs is lacking. The singular problem of brain 
death is discussed later. 

The locked-in state describes yet another type of 
pseudocoma in which an awake patient has no means of 
producing speech or volitional movement, but retains 
voluntary vertical eye movements and lid elevation, thus 
allowing the patient to signal -with a clear mind. The 
pupils are normally reactive. Such individuals have writ- 
ten entire treatises using Morse code. The usual cause is 
an infarction or hemorrhage of the ventral pons, which 
transects all descending corticospinal and corticobulbar 
pathways. A similar awake but de-efferented state occurs 
as a result of total paralysis of the musculature in severe 
cases of Guillain-Barre syndrome (Chap. 41), critical ill- 
ness neuropathy (Chap. 22), and pharmacologic neuro- 
muscular blockade. 

THE ANATOMY AND PHYSIOLOGY 
OF COMA 

Almost all instances of diminished alertness can be traced 
to widespread abnormalities of the cerebral hemispheres 
or to reduced activity of a special thalamocortical alert- 
ing system termed the reticular activating system. The 
proper functioning of this system, its ascending projec- 
tions to the cortex, and the cortex itself are required to 
maintain alertness and coherence of thought. It follows 
that the principal causes of coma are (1) lesions that 



damage the RAS or its projections; (2) destruction of 131 
large portions of both cerebral hemispheres; and (3) sup- 
pression of reticulo-cerebral function by drugs, toxins, or 
metabolic derangements such as hypoglycemia, anoxia, 
uremia, and hepatic failure. 

The proximity of the RAS to structures that control 
pupillary function and eye movements permits clinical 
localization of the cause of coma in many cases. Pupillary 
enlargement with loss of light reaction and loss of verti- 
cal and adduction movements of the eyes suggests that 
the likely location of the lesion is in the upper brainstem. 
Conversely, preservation of pupillary reactivity and eye 
movements absolves the upper brainstem and indicates 
that widespread structural lesions or metabolic suppres- 
sion of the cerebral hemispheres is responsible. 



Coma Due to Cerebral Mass Lesions 
and Herniations 

The cranial cavity is separated into compartments by 
infoldings of the dura. The two cerebral hemispheres are 
separated by the falx, and the anterior and posterior fos- 
sae by the tentorium. Herniation refers to displacement 
of brain tissue into a compartment that it normally does 
not occupy. Many of the signs associated -with coma, and 
indeed coma itself, can be attributed to these tissue 
shifts, and certain clinical configurations are characteristic 
of specific herniations (Fig. 14-1). They are in essence 
"false localizing" signs since they derive from compres- 
sion of brain structures at a distance from the mass. 




r- 1 
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FIGURE 14-1 

Types of cerebral herniation. 

(C) transfalcial; (D) foraminal. 



(A) uncal; (B) central; 



132 



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The most common herniations are from the supra- 
tentorial to the infratentorial compartments through 
the tentorial opening, hence transtentorial. Uncal transten- 
torial herniation refers to impaction of the anterior 
medial temporal gyrus (the uncus) into the tentorial 
opening just anterior to and adjacent to the midbrain 
(Fig. 14-1, A). The displaced brain tissue compresses the 
third nerve as it traverses the subarachnoid space, and 
results in enlargement of the ipsilateral pupil (putatively 
because the fibers subserving parasympathetic pupillary 
function are located peripherally in the nerve). The 
coma that follows is due to compression of the mid- 
brain against the opposite tentorial edge by the dis- 
placed parahippocampal gyrus (Fig. 14-2). In some 
cases, the lateral displacement of the midbrain causes 
compression of the opposite cerebral peduncle, produc- 
ing a Babinski sign and hemiparesis contralateral to the 
original hemiparesis (the Kernohan-Woltman sign). In 
addition to compressing the upper brainstem, tissue 
shifts, including herniations, may compress major blood 
vessels, particularly the anterior and posterior cerebral 
arteries as they pass over the tentorial reflections, thus 
producing brain infarctions. The distortions may also 
entrap portions of the ventricular system, resulting in 
regional hydrocephalus. 

Central transtentorial herniation denotes a symmetric 
downward movement of the thalamic medial structures 
through the tentorial opening with compression of 
the upper midbrain (Fig. 14-1, B). Miotic pupils and 




A B 

FIGURE 14-2 

Coronal (A) and axial (B) magnetic resonance images from 
a stuporous patient with a left third nerve palsy as a result of 
a large left-sided subdural hematoma (seen as a gray-white rim). 
The upper midbrain and lower thalamic regions are com- 
pressed and displaced horizontally away from the mass, and 
there is transtentorial herniation of the medial temporal lobe 
structures, including the uncus anteriorly. The lateral ventricle 
opposite to the hematoma has become enlarged as a result of 
compression of the third ventricle. 



drowsiness are the heralding signs. Both temporal and 
central herniations have classically been considered to 
cause a progressive compression of the brainstem from 
above in an orderly manner: first the midbrain, then the 
pons, and finally the medulla. The result is a sequence of 
neurologic signs that corresponds to each affected level. 
Other forms of herniation are transfalcial herniation (dis- 
placement of the cingulate gyrus under the fafx and 
across the midline, Fig. 14-1, C), and foraminal herniation 
(downward forcing of the cerebellar tonsils into the 
foramen magnum, Fig. 14-1, D), -which causes compres- 
sion of the medulla and respiratory arrest. 

A direct relationship between the various configura- 
tions of transtentorial herniations and coma is not 
always found. Drowsiness and stupor typically occur 
-with moderate horizontal shifts at the level of the dien- 
cephalon (thalami) well before transtentorial or other 
herniations are evident. Lateral shift may be quantified 
on axial images of CT and MRI scans (Fig. 14-2). In 
cases of acutely appearing masses, horizontal displacement 
of the pineal calcification of 3—5 mm is generally associ- 
ated with drowsiness, 6-8 mm with stupor, and >9 mm 
with coma. Intrusion of the medial temporal lobe into 
the tentorial opening may be apparent on MRI and CT 
scans by an obliteration of the cisterns that surround the 
upper brainstem. 

Coma Due to Metabolic Disorders 

Many systemic metabolic abnormalities cause coma by 
interrupting the delivery of energy substrates (hypoxia, 
ischemia, hypoglycemia) or by altering neuronal excitabil- 
ity (drug and alcohol intoxication, anesthesia, and epilepsy) . 
The same metabolic abnormalities that produce coma 
may in milder form induce widespread cortical dysfunc- 
tion and an acute confusional state. Thus, in metabolic 
encephalopathies, clouded consciousness and coma are in 
a continuum. 

Cerebral neurons are fully dependent on cerebral 
blood flow (CBF) and the related delivery of oxygen 
and glucose. CBF is ~75 mL per 100 g/min in gray mat- 
ter and 30 mL per 100 g/min in white matter (mean = 
55 mL per 100 g/min); oxygen consumption is 3.5 mL per 
100 g/min, and glucose utilization is 5 mg per 100 g/min. 
Brain stores of glucose provide energy for ~2 min after 
blood flow is interrupted, and oxygen stores last 8—10 s 
after the cessation of blood flow. Simultaneous hypoxia 
and ischemia exhaust glucose more rapidly. The elec- 
troencephalogram (EEC) rhythm in these circum- 
stances becomes diffusely slowed, typical of metabolic 
encephalopathies, and as conditions of substrate delivery 
worsen, eventually all recordable brain electrical activity 
ceases. In almost all instances of metabolic encephalo- 
pathy, the global metabolic activity of the brain is 
reduced in proportion to the degree of diminished 
consciousness. 



Conditions such as hypoglycemia, hyponatremia, 
hyperosmolarity, hypercapnia, hypercalcemia, and hepatic 
and renal failure are associated with a variety of alter- 
ations in neurons and astrocytes. Unlike hypoxia-ischemia, 
which causes neuronal destruction, metabolic disorders 
generally cause only minor neuropathologic changes. 
The reversible effects of these conditions on the brain 
are not understood but may result from impaired energy 
supplies, changes in ion fluxes across neuronal mem- 
branes, and neurotransmitter abnormalities. For example, 
the high brain ammonia concentration of hepatic coma 
interferes with cerebral energy metabolism and with the 
Na + , K + -ATPase pump, increases the number and size of 
astrocytes, alters nerve cell function, and causes increased 
concentrations of potentially toxic products of ammonia 
metabolism; it may also result in abnormalities of neuro- 
transmitters, including putative "false" neurotransmitters 
that are active at receptor sites. Apart from hyperammone- 
mia, which of these mechanisms is of critical impor- 
tance is not clear. The mechanism of the encephalopathy 
of renal failure is also not known. Unlike ammonia, urea 
itself does not produce central nervous system (CNS) 
toxicity. A multifactorial causation has been proposed, 
including increased permeability of the blood-brain bar- 
rier to toxic substances such as organic acids and an increase 
in brain calcium or cerebrospinal fluid (CSF) phosphate 
content. 

Coma and seizures are a common accompaniment of 
any large shifts in sodium and water balance in the brain. 
These changes in osmolarity arise from systemic medical 
disorders including diabetic ketoacidosis, the nonketotic 
hyperosmolar state, and hyponatremia from any cause 
(e.g., water intoxication, excessive secretion of antidi- 
uretic hormone or atrial natriuretic peptides). Sodium 
levels <125 mmol/L induce confusion, and <115 mmol/L 
are associated with coma and convulsions. In hyperosmo- 
lar coma the serum osmolarity is generally >350 
mosmol/L. Hypercapnia depresses the level of conscious- 
ness in proportion to the rise in C0 2 tension in the 
blood. In all of these metabolic encephalopathies, the degree of 
neurologic change depends to a large extent on the rapidity with 
which the serum changes occur. The pathophysiology of 
other metabolic encephalopathies such as hypercalcemia, 
hypothyroidism, vitamin B 12 deficiency, and hypothermia 
are incompletely understood but must also reflect 
derangements of CNS biochemistry and membrane 
function. 

Epileptic Coma 

Continuous, generalized electrical discharges of the cor- 
tex {seizures) are associated with coma even in the absence 
of epileptic motor activity {convulsions). The self-limited 
coma that follows seizures, termed the postictal state, may 
be due to exhaustion of energy reserves or effects of 
locally toxic molecules that are the byproduct of seizures. 



The postictal state produces a pattern of continuous, gen- 133 
eralized slowing of the background EEC activity similar 
to that of other metabolic encephalopathies. 

Toxic Drug-Induced Coma 

This common class of encephalopathy is in large mea- 
sure reversible and leaves no residual damage providing 
hypoxia does not supervene. Many drugs and toxins are 
capable of depressing nervous system function. Some 
produce coma by affecting both the brainstem nuclei, 
including the RAS, and the cerebral cortex. The combi- 
nation of cortical and brainstem signs, which occurs in 
certain drug overdoses, may lead to an incorrect diagno- 
sis of structural brainstem disease. Overdose of medica- 
tions that have atropinic actions produces physical signs 
such as dilated pupils, tachycardia, and dry skin. 



Coma Due to Widespread Damage to the 
Cerebral Hemispheres 

This special category, comprising a number of unrelated 
disorders, results from widespread structural cerebral 
damage, thereby simulating a metabolic disorder of the 
cortex. The effect of prolonged hypoxia-ischemia is per- 
haps the best known and one in which it is not possible 
to distinguish the acute effects of hypoperfusion of the 
brain from the further effects of generalized neuronal 
damage. Similar bihemispheral damage is produced by 
disorders that occlude small blood vessels throughout 
the brain; examples include cerebral malaria, thrombotic 
thrombocytopenic purpura, and hyperviscosity. The pres- 
ence of seizures and the bihemispheral damage are some- 
times an indication of this class of disorder. 



Approach to the Patient: 

COMA 



Acute respiratory and cardiovascular problems should 
be attended to prior to neurologic assessment. In 
most instances, a complete medical evaluation, except 
for vital signs, funduscopy, and examination for 
nuchal rigidity, may be deferred until the neurologic 
evaluation has established the severity and nature of 
coma. The approach to the patient with cranial 
trauma is discussed in Chap. 31. 

HISTORY In many cases, the cause of coma is 
immediately evident (e.g., trauma, cardiac arrest, or 
known drug ingestion). In the remainder, certain 
points are especially useful: (1) the circumstances and 
rapidity with which neurologic symptoms developed; 
(2) the antecedent symptoms (confusion, weakness, 
headache, fever, seizures, dizziness, double vision, or 



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vomiting); (3) the use of medications, illicit drugs, or 
alcohol; and (4) chronic liver, kidney, lung, heart, or 
other medical disease. Direct interrogation of family 
and observers on the scene, in person or by tele- 
phone, is an important part of the initial evaluation. 
Ambulance technicians often provide the most useful 
information. 

GENERAL PHYSICAL EXAMINATION The 

temperature, pulse, respiratory rate and pattern, and 
blood pressure should be measured quickly. Fever 
suggests a systemic infection, bacterial meningitis, or 
encephalitis; only rarely is it attributable to a brain 
lesion that has disturbed hypothalamic temperature- 
regulating centers ("central fever"). A slight elevation in 
temperature may follow vigorous convulsions. High 
body temperature, 42°-44°C, associated with dry skin 
should arouse the suspicion of heat stroke or anti- 
cholinergic drug intoxication. Hypothermia is observed 
with alcoholic, barbiturate, sedative, or phenothiazine 
intoxication; hypoglycemia; peripheral circulatory 
failure; or hypothyroidism. Hypothermia itself causes 
coma only when the temperature is <31°C. Tachyp- 
nea may indicate systemic acidosis or pneumonia. 
Aberrant respiratory patterns that reflect brainstem 
disorders are discussed later. Marked hypertension 
either indicates hypertensive encephalopathy or is the 
result of a rapid rise in intracranial pressure (ICP; the 
Cushing response) most often after cerebral hemor- 
rhage or head injury. Hypotension is characteristic of 
coma from alcohol or barbiturate intoxication, inter- 
nal hemorrhage, myocardial infarction, sepsis, pro- 
found hypothyroidism, or Addisonian crisis. 

The funduscopic examination can detect subarachnoid 
hemorrhage (subhyaloid hemorrhages), hypertensive 
encephalopathy (exudates, hemorrhages, vessel-crossing 
changes, papilledema), and increased ICP (papilledema). 
Cutaneous petechiae suggest thrombotic thrombocy- 
topenic purpura, meningococcemia, or a bleeding 
diathesis from which an intracerebral hemorrhage has 
arisen. 

NEUROLOGIC EXAMINATION First, the patient 
should be observed without intervention by the exam- 
iner. Tossing about in the bed, reaching up toward the 
face, crossing legs, yawning, swallowing, coughing, or 
moaning denotes a state close to normal awakeness. 
Lack of restless movements on one side or an out- 
turned leg suggests a hemiplegia. Intermittent twitch- 
ing movements of a foot, finger, or facial muscle may 
be the only sign of seizures. Multifocal myoclonus 
almost always indicates a metabolic disorder, particu- 
larly uremia, anoxia, or drug intoxication (lithium and 
haloperidol are particularly likely to cause this sign), or 
the rare conditions of a prion disease (Chap. 38) or 
"Hashimoto encephalopathy." In a drowsy and confused 



patient bilateral asterixis is a certain sign of metabolic 
encephalopathy or drug intoxication. 

The terms decorticate rigidity and decerebrate rigidity, 
or "posturing," describe stereotyped arm and leg 
movements occurring spontaneously or elicited by 
sensory stimulation. Flexion of the elbows and wrists 
and supination of the arm (decortication) suggests 
bilateral damage rostral to the midbrain, whereas 
extension of the elbows and wrists with pronation 
(decerebration) indicates damage to motor tracts in 
the midbrain or caudal diencephalon. The less fre- 
quent combination of arm extension with leg flexion 
or flaccid legs is associated with lesions in the pons. 
These concepts have been adapted from animal work 
and cannot be applied with the same precision to 
coma in humans. In fact, acute and widespread disor- 
ders of any type, regardless of location, frequently 
cause limb extension, and almost all such extensor 
posturing becomes predominantly flexor as time 
passes. Posturing may also be unilateral and may 
coexist with purposeful limb movements, usually 
reflecting incomplete damage to the motor system. 

LEVEL OF AROUSAL A sequence of increasingly 
intense stimuli is used to determine the threshold for 
arousal and the optimal motor response of each side 
of the body. The results of testing may vary from 
minute to minute and serial examinations are most 
useful. Tickling the nostrils with a cotton wisp is a 
moderate stimulus to arousal — all but deeply stu- 
porous and comatose patients will move the head 
away and rouse to some degree. Using the hand to 
remove the offending stimulus represents an even 
greater degree of responsiveness. Stereotyped postur- 
ing in response to noxious stimuli indicates severe 
dysfunction of the corticospinal system. Abduction- 
avoidance movement of a limb is usually purposeful 
and denotes an intact corticospinal system. Pressure 
on the knuckles or bony prominences and pinprick 
stimulation are humane forms of noxious stimuli; 
pinching the skin causes unsightly ecchymoses and is 
generally not necessary but may be useful in eliciting 
abduction withdrawal movements of the limbs. 

BRAINSTEM REFLEXES Assessment of brainstem 
function is essential to localization of the lesion in coma 
(Fig. 14-3). The brainstem reflexes that are conve- 
niently examined are pupillary responses to light, spon- 
taneous and elicited eye movements, corneal responses, 
and the respiratory pattern. As a rule, when these brain- 
stem activities are preserved, particularly the pupil reac- 
tions and eye movements, coma must be ascribed to 
bilateral hemispheral disease. The converse, however, is 
not always true, as a mass in the hemispheres may be 
the underlying cause of coma but nonetheless produce 
brainstem signs by inducing transtentorial herniation. 



Pupillary light reflex 




FIGURE 14-3 

Examination of brainstem reflexes in coma. Midbrain and 
third nerve function are tested by pupillary reaction to light, 
pontine function by spontaneous and reflex eye movements 
and corneal responses, and medullary function by respiratory 
and pharyngeal responses. Reflex conjugate, horizontal eye 
movements are dependent on the medial longitudinal fasci- 
culus (MLF) interconnecting the sixth and contralateral third 
nerve nuclei. Head rotation (oculocephalic reflex) or caloric 
stimulation of the labyrinths (oculovestibular reflex) elicits 
contraversive eye movements (for details see text). 



Pupillary Signs Pupillary reactions are examined 
with a bright, diffuse light (not an ophthalmoscope); if 
the response is absent, this should be confirmed by 
observation through a magnifying lens. Normally 
reactive and round pupils of midsize (2.5—5 mm) 
essentially exclude midbrain damage, either primary 
or secondary to compression. Reaction to light is 
often difficult to appreciate in pupils <2 mm in diam- 
eter, and bright room lighting mutes pupillary reactiv- 
ity. One unreactive and enlarged pupil (>6 mm) or 
one that is poorly reactive signifies compression of the 
third nerve from the effects of a mass above. Enlarge- 
ment of the pupil contralateral to a mass may occur 
first but is infrequent. An oval and slightly eccentric 



pupil is a transitional sign that accompanies early 
midbrain— third nerve compression. The most extreme 
pupillary sign, bilaterally dilated and unreactive pupils, 
indicates severe midbrain damage, usually from com- 
pression by a supratentorial mass. Ingestion of drugs 
with anticholinergic activity, the use of mydriatic eye 
drops, and direct ocular trauma are among the causes 
of misleading pupillary enlargement. 

Unilateral miosis in coma has been attributed to 
dysfunction of sympathetic efferents originating in 
the posterior hypothalamus and descending in the 
tegmentum of the brainstem to the cervical cord. It is 
an occasional finding with a large cerebral hemor- 
rhage that affects the thalamus. Reactive and bilater- 
ally small (1—2.5 mm) but not pinpoint pupils are 
seen in metabolic encephalopathies or in deep bilat- 
eral hemispheral lesions such as hydrocephalus or 
thalamic hemorrhage. Very small but reactive pupils 
(<1 mm) characterize narcotic or barbiturate over- 
doses but also occur with extensive pontine hemor- 
rhage. The response to naloxone and the presence of 
reflex eye movements (see below) distinguish these. 

Ocular Movements The eyes are first observed 
by elevating the lids and noting the resting position 
and spontaneous movements of the globes. Lid tone, 
tested by lifting the eyelids and noting their resistance 
to opening and the speed of closure, is reduced pro- 
gressively as coma deepens. Horizontal divergence of 
the eyes at rest is normal in drowsiness. As coma 
deepens, the ocular axes may become parallel again. 

Spontaneous eye movements in coma often take 
the form of conjugate horizontal roving. This finding 
alone exonerates the midbrain and pons and has the 
same significance as normal reflex eye movements 
(see below). Conjugate horizontal ocular deviation to 
one side indicates damage to the pons on the oppo- 
site side or alternatively to the frontal lobe on the 
same side. This phenomenon is summarized by the 
following maxim: The eyes look toward a hemispheral 
lesion and away from a brainstem lesion. Seizures also 
drive the eyes to one side. On rare occasions, the eyes 
may turn paradoxically away from the side of a deep 
hemispheral lesion ("wrong- way eyes"). The eyes 
turn down and inward as a result of thalamic and 
upper midbrain lesions, typically with thalamic hem- 
orrhage. "Ocular bobbing" describes brisk downward 
and slow upward movements of the eyes associated 
with loss of horizontal eye movements and is diag- 
nostic of bilateral pontine damage, usually from 
thrombosis of the basilar artery. "Ocular dipping" is a 
slower, arrhythmic downward movement followed by 
a faster upward movement in patients with normal 
reflex horizontal gaze; it indicates diffuse cortical 
anoxic damage. Many other complex eye movements 



135 



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are known but do not have the same clinical impor- 
tance as those mentioned earlier. 

The oculocephalic reflexes depend on the integrity 
of the ocular motor nuclei and their interconnecting 
tracts that extend from the midbrain to the pons and 
medulla. These reflexes are elicited by moving the 
head from side to side or vertically and observing 
evoked eye movements in the direction opposite to 
the head movement (Fig. 14-3). The movements, 
called somewhat inappropriately "doll's eyes" (which 
refers more accurately to the reflex elevation of the 
eyelids with flexion of the neck), are normally sup- 
pressed in the awake patient. The ability to elicit them 
therefore indicates a reduced cortical influence on the 
brainstem. Furthermore, preservation of evoked reflex 
eye movements signifies the integrity of the brainstem 
and implies that the origin of unconsciousness lies in 
the cerebral hemispheres. The opposite, an absence of 
reflex eye movements, usually signifies damage within 
the brainstem but can be produced infrequently by 
profound overdoses of certain drugs. Normal pupillary 
size and light reaction distinguishes most drug- 
induced comas from structural brainstem damage. 

Thermal, or "caloric," stimulation of the vestibular 
apparatus (oculovestibular response) provides a more 
intense stimulus for the oculocephalic reflex but gives 
fundamentally the same information. The test is per- 
formed by irrigating the external auditory canal with 
cool water in order to induce convection currents in 
the labyrinths. After a brief latency, the result is tonic 
deviation of both eyes to the side of cool- water irriga- 
tion and nystagmus in the opposite direction. (The 
acronym "COWS" has been used to remind generations 
of medical students of the direction of nystagmus — 
"cold water opposite, warm water same.") The loss of 
conjugate ocular movements indicates brainstem dam- 
age. The absence of nystagmus despite conjugate devia- 
tion of the globes indicates that the cerebral hemispheres 
are damaged or metabolically suppressed. 

By touching the cornea with a wisp of cotton, a 
response consisting of brief bilateral lid closure is nor- 
mally observed. The corneal reflexes depend on the 
integrity of pontine pathways between the fifth 
(afferent) and both seventh (efferent) cranial nerves; 
although rarely useful alone, in conjunction with 
reflex eye movements they are important clinical tests 
of pontine function. CNS depressant drugs diminish 
or eliminate the corneal responses soon after reflex 
eye movements are paralyzed but before the pupils 
become unreactive to light. The corneal (and pharyn- 
geal) response may be lost for a time on the side of an 
acute hemiplegia. 

Respiratory Patterns These are of less localiz- 
ing value in comparison to other brainstem signs. 



Shallow, slow, but regular breathing suggests metabolic 
or drug depression. Cheyne-Stokes respiration in its 
classic cyclic form, ending with a brief apneic period, 
signifies bihemispheral damage or metabolic suppres- 
sion and commonly accompanies light coma. Rapid, 
deep (Kussmaul) breathing usually implies metabolic 
acidosis but may also occur with pontomesencephalic 
lesions. Agonal gasps are the result of lower brainstem 
(medullary) damage and are well known as the termi- 
nal respiratory pattern of severe brain damage. A num- 
ber of other cyclic breathing variations have been 
described but are of lesser significance. 



LABORATORY STUDIES AND IMAGING 

The studies that are most useful in the diagnosis of coma 
are: chemical-toxicologic analysis of blood and urine, 
cranial CT or MRI, EEG, and CSF examination. Arter- 
ial blood-gas analysis is helpful in patients with lung dis- 
ease and acid-base disorders. The metabolic aberrations 
commonly encountered in clinical practice require mea- 
surements of electrolytes, glucose, calcium, osmolarity, 
and renal (blood urea nitrogen) and hepatic (NH 3 ) func- 
tion. Toxicologic analysis is necessary in any case of 
coma where the diagnosis is not immediately clear. 
However, the presence of exogenous drugs or toxins, 
especially alcohol, does not exclude the possibility that 
other factors, particularly head trauma, are also contribut- 
ing to the clinical state. An ethanol level of 43 mmol/L 
(0.2 g/dL) in nonhabituated patients generally causes 
impaired mental activity and of >65 mmol/L (0.3 g/dL) 
is associated with stupor. The development of tolerance 
may allow the chronic alcoholic to remain awake at levels 
>87 mmol/L (0.4 g/dL). 

The availability of CT and MRI has focused attention 
on causes of coma that are radiologically detectable (e.g., 
hemorrhages, tumors, or hydrocephalus). Resorting pri- 
marily to this approach, although at times expedient, is 
imprudent because most cases of coma (and confusion) 
are metabolic or toxic in origin. The notion that a normal 
CT scan excludes anatomic lesions as the cause of coma is 
also erroneous. Bilateral hemisphere infarction, acute 
brainstem infarction, encephalitis, meningitis, mechanical 
shearing of axons as a result of closed head trauma, sagittal 
sinus thrombosis, and subdural hematomas that are iso- 
dense to adjacent brain are some of the disorders that may 
not be detected. Nevertheless, if the source of coma 
remains unknown, a scan should be obtained. 

The EEG is useful in metabolic or drug-induced states 
but is rarely diagnostic, except when coma is due to clini- 
cally unrecognized seizures, to herpesvirus encephalitis, or 
to prion (Creutzfeldt-Jakob) disease. The amount of back- 
ground slowing of the EEG is a reflection of the severity 
of any diffuse encephalopathy. Predominant high-voltage 



slowing (8 or triphasic waves) in the frontal regions is 
typical of metabolic coma, as from hepatic failure, and 
widespread fast ((3) activity implicates sedative drugs (e.g., 
diazepines, barbiturates). A special pattern of "alpha coma," 
defined by widespread, variable 8- to 12-Hz activity, 
superficially resembles the normal OC rhythm of waking 
but is unresponsive to environmental stimuli. It results 
from pontine or diffuse cortical damage and is associated 
with a poor prognosis. Most importantly, EEG recordings 
may reveal clinically inapparent epileptic discharges in a 
patient with coma. Normal OC activity on the EEG, which 
is suppressed by stimulating the patient, also alerts the 
clinician to the locked-in syndrome or to hysteria or 
catatonia. 

Lumbar puncture is performed less frequently than in the 
past for coma diagnosis because neuroimaging effectively 
excludes intracerebral and extensive subarachnoid hemor- 
rhage. However, examination of the CSF remains indis- 
pensable in the diagnosis of meningitis and encephalitis. 



Lumbar puncture should therefore not be deferred if 137 
meningitis is a possibility. 

DIFFERENTIAL DIAGNOSIS OF COMA 

(Table 14-1) The causes of coma can be divided into 
three broad categories: those without focal neurologic 
signs (e.g., metabolic encephalopathies); meningitis syn- 
dromes, characterized by fever or stiff neck and an 
excess of cells in the spinal fluid (e.g., bacterial meningi- 
tis, subarachnoid hemorrhage); and conditions associated 
with prominent focal signs (e.g., stroke, cerebral hemor- 
rhage). In most instances coma is part of an obvious 
medical problem such as drug ingestion, hypoxia, stroke, 
trauma, or liver or kidney failure. Conditions that cause 
sudden coma include drug ingestion, cerebral hemorrhage, 
trauma, cardiac arrest, epilepsy, or basilar artery embolism. 
Coma that appears subacutely is usually related to a 
preceding medical or neurologic problem, including the 



TABLE 14-1 



DIFFERENTIAL DIAGNOSIS OF COMA 



Diseases that cause no focal or lateralizing neurologic signs, usually with normal brainstem functions; CT scan and cellular 
content of the CSF are normal 

a. Intoxications: alcohol, sedative drugs, opiates, etc. 

b. Metabolic disturbances: anoxia, hyponatremia, hypernatremia, hypercalcemia, diabetic acidosis, nonketotic 
hyperosmolar hyperglycemia, hypoglycemia, uremia, hepatic coma, hypercarbia, addisonian crisis, hypo- and 
hyperthyroid states, profound nutritional deficiency 

c. Severe systemic infections: pneumonia, septicemia, typhoid fever, malaria, Waterhouse-Friderichsen syndrome 

d. Shock from any cause 

e. Postseizure states, status epilepticus, subclinical epilepsy 

f. Hypertensive encephalopathy, eclampsia 

g. Severe hyperthermia, hypothermia 
h. Concussion 

i. Acute hydrocephalus 

Diseases that cause meningeal irritation with or without fever, and with an excess of WBCs or RBCs in the CSF, usually 
without focal or lateralizing cerebral or brainstem signs; CT or MRI shows no mass lesion 

a. Subarachnoid hemorrhage from ruptured aneurysm, arteriovenous malformation, trauma 

b. Acute bacterial meningitis 

c. Viral encephalitis 

d. Miscellaneous: Fat embolism, cholesterol embolism, carcinomatous and lymphomatous meningitis, etc. 
Diseases that cause focal brainstem or lateralizing cerebral signs, with or without changes in the CSF; CT and MRI are 
abnormal 

a. Hemispheral hemorrhage (basal ganglionic, thalamic) or infarction (large middle cerebral artery territory) with secondary 
brainstem compression 

b. Brainstem infarction due to basilar artery thrombosis or embolism 

c. Brain abscess, subdural empyema 

d. Epidural and subdural hemorrhage, brain contusion 

e. Brain tumor with surrounding edema 

f. Cerebellar and pontine hemorrhage and infarction 

g. Widespread traumatic brain injury 

h. Metabolic coma (see above) with preexisting focal damage 

i. Miscellaneous: cortical vein thrombosis, herpes simplex encephalitis, multiple cerebral emboli due to bacterial 
endocarditis, acute hemorrhagic leukoencephalitis, acute disseminated (postinfectious) encephalomyelitis, thrombotic 
thrombocytopenic purpura, cerebral vasculitis, gliomatosis cerebri, pituitary apoplexy, intravascular lymphoma, etc. 



Note: CSF, cerebrospinal fluid; WBCs, white blood cells; RBCs, red blood cells. 



138 



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secondary brain swelling of a mass lesion such as tumor 
or cerebral infarction. 

Cerebrovascular diseases cause the greatest difficulty in 
coma diagnosis (Chap. 21). The most common categories 
are: (1) basal ganglia and thalamic hemorrhage (acute but 
not instantaneous onset, vomiting, headache, hemiplegia, 
and characteristic eye signs); (2) pontine hemorrhage (sud- 
den onset, pinpoint pupils, loss of reflex eye movements and 
corneal responses, ocular bobbing, posturing, hyperventila- 
tion, and excessive sweating); (3) cerebellar hemorrhage 
(occipital headache, vomiting, gaze paresis, and inability to 
stand); (4) basilar artery thrombosis (neurologic prodrome or 
warning spells, diplopia, dysarthria, vomiting, eye movement 
and corneal response abnormalities, and asymmetric limb 
paresis); and (5) subarachnoid hemorrhage (precipitous 
coma after headache and vomiting). The most common 
stroke, infarction in the territory of the middle cerebral 
artery, does not generally cause coma, but edema surround- 
ing large infarcts may expand during the first few days and 
act as a mass. The syndrome of acute hydrocephalus accom- 
panies many intracranial diseases, particularly subarachnoid 
hemorrhage. It is characterized by headache and sometimes 
vomiting that may progress quickly to coma, with extensor 
posturing of the limbs, bilateral Babinski signs, small unreac- 
tive pupils, and impaired oculocephalic movements in the 
vertical direction. 

If the history and examination do not indicate the 
cause of coma, then information obtained from CT or 
MRI may be needed. The majority of medical causes of 
coma can be established without a neuroimaging study. 

BRAIN DEATH 

This is a state of cessation of cerebral function while 
somatic function is maintained by artificial means and 
the heart continues to pump. It is the only type of brain 
damage that is recognized as equivalent to death. Several 
similar criteria have been advanced for the diagnosis of 
brain death, and it is essential to adhere to those standards 
endorsed by the local medical community. Ideal criteria 
are simple, can be assessed at the bedside, and allow no 
chance of diagnostic error. They contain three essential 
elements of clinical evidence: (1) widespread cortical 
destruction that is reflected by deep coma and unrespon- 
siveness to all forms of stimulation; (2) global brainstem 
damage demonstrated by absent pupillary light reaction 
and by the loss of oculovestibular and corneal reflexes; 
and (3) destruction of the medulla manifested by com- 
plete apnea. The pulse rate is invariant and unresponsive 
to atropine. Diabetes insipidus is often present but may 
develop hours or days after the other clinical signs of 
brain death. The pupils are often enlarged but may be 
mid-sized; they should not, however, be constricted. The 
absence of deep tendon reflexes is not required because 
the spinal cord remains functional. There may or may not 
be Babinski signs. 



Demonstration that apnea is due to irreversible 
medullary damage requires that the P C o2 be high 
enough to stimulate respiration during a test of sponta- 
neous breathing. Apnea testing can be done safely by the 
use of diffusion oxygenation prior to removing the ven- 
tilator. This is accomplished by preoxygenation with 
1 00% oxygen, which is then sustained during the test by 
oxygen administered through a tracheal cannula. C0 2 
tension increases ~0.3— 0.4 kPa/min (2—3 mm Hg/min) 
during apnea. At the end of the period of observation, 
typically several minutes, arterial P C o2 should be at least 
>6. 6-8.0 kPa (50-60 mm Hg) for the test to be valid. 
Apnea is confirmed if no respiratory effort is observed 
in the presence of a sufficiently elevated Pco2- 

The possibility of profound drug-induced or hypother- 
mic depression of the nervous system should be excluded, 
and some period of observation, usually 6—24 h, is desir- 
able during which the signs of brain death are sustained. It 
is advisable to delay clinical testing for at least 24 h if a car- 
diac arrest has caused brain death or if the inciting disease 
is not known. An isoelectric EEC may be used as a confir- 
matory test for total cerebral damage. Radionuclide brain 
scanning, cerebral angiography, or transcranial Doppler 
measurements may also be used to demonstrate the 
absence of cerebral blood flow but they have not been 
extensively correlated with pathologic changes. 

Although it is largely accepted in western society that 
the respirator can be disconnected from a brain-dead 
patient, problems frequently arise because of poor com- 
munication and inadequate preparation of the family by 
the physician. Reasonable medical practice allows the 
removal of support or transfer out of an intensive care 
unit of patients who are not brain dead but whose con- 
dition is nonetheless hopeless and are likely to live for 
only a brief time. 



"k 



Treatment: 
COMA 



The immediate goal in a comatose patient is prevention 
of further nervous system damage. Hypotension, hypo- 
glycemia, hypercalcemia, hypoxia, hypercapnia, and 
hyperthermia should be corrected rapidly. An oropha- 
ryngeal airway is adequate to keep the pharynx open in 
drowsy patients who are breathing normally. Tracheal 
intubation is indicated if there is apnea, upper airway 
obstruction, hypoventilation, or emesis, or if the patient 
is liable to aspirate because of coma. Mechanical ventila- 
tion is required if there is hypoventilation or a need to 
induce hypocapnia in order to lower ICP as described 
below. IV access is established, and naloxone and dextrose 
are administered if narcotic overdose or hypoglycemia are 
even remote possibilities; thiamine is given along with 



glucose to avoid provoking Wernicke disease in malnour- 
ished patients. In cases of suspected basilar thrombosis 
with brainstem ischemia, IV heparin or a thrombolytic 
agent is often utilized, after cerebral hemorrhage has 
been excluded by a neuroimaging study. Physostigmine 
may awaken patients with anticholinergic-type drug 
overdose but should be used only by experienced 
physicians and with careful monitoring; many physi- 
cians believe that it should only be used to treat anti- 
cholinergic overdose-associated cardiac arrhythmias. 
The use of benzodiazepine antagonists offers some 
prospect of improvement after overdoses of soporific 
drugs and has transient benefit in hepatic encephalopa- 
thy. IV administration of hypotonic solutions should be 
monitored carefully in any serious acute brain illness 
because of the potential for exacerbating brain swelling. 
Cervical spine injuries must not be overlooked, particu- 
larly prior to attempting intubation or evaluating of ocu- 
locephalic responses. Fever and meningismus indicate 
an urgent need for examination of the CSF to diagnose 
meningitis. If the lumbar puncture in a case of sus- 
pected meningitis is delayed for any reason, an antibi- 
otic such as a third-generation cephalosporin should be 
administered as soon as possible, preferably after 
obtaining blood cultures. The management of raised ICP 
is discussed in Chap. 22. 



PROGNOSIS 

One hopes to avoid the emotionally painful, hopeless 
outcome of a patient who is left severely disabled or 



vegetative. The uniformly poor outcome of the persis- 
tent vegetative state has already been mentioned. Chil- 
dren and young adults may have ominous early clinical 
findings such as abnormal brainstem reflexes and yet 
recover, so that temporization in offering a prognosis in 
this group of patients is wise. Metabolic comas have a far 
better prognosis than traumatic ones. All systems for esti- 
mating prognosis in adults should be taken as approxi- 
mations, and medical judgments must be tempered by 
factors such as age, underlying systemic disease, and gen- 
eral medical condition. In an attempt to collect prognos- 
tic information from large numbers of patients with 
head injury, the Glasgow Coma Scale was devised; 
empirically it has predictive value in cases of brain 
trauma (Table 31-2). For anoxic and metabolic coma, 
clinical signs such as the pupillary and motor responses 
after 1 day, 3 days, and 1 week have been shown to have 
predictive value (Fig. 22-4) . The absence of the cortical 
waves of the somatosensory evoked potentials has also 
proved a strong indicator of poor outcome in coma 
from any cause. 

FURTHER READINGS 

LAUREYS S et al: Brain function in coma, vegetative state, and related 

disorders. Lancet Neurol 3:537, 2004 
POSNER JB et al: Plum and Posner's Diagnosis of Stupor and Coma, 4th ed. 

New York and London, Oxford Univ Press, 2007 
ROPPER AH: Neurological and Neurosurgical Intensive Care, 4th ed. New 

York, Lippincott Williams & Wilkins, 2004 
WlJDICKS EF et al: Neuropathology of brain death in the modern 

transplant era. Neurology 70:1234, 2008 
YOUNG GB: Clinical Practice. Neurologic prognosis after cardiac 

arrest. N Engl J Med 361:605, 2009 



139 




M. -Marsel Mesulam 



The Left Perisylvian Network for Language: 

Aphasias and Related Conditions 140 

Clinical Examination 141 

The Parietofrontal Network for Spatial Orientation: 

Neglect and Related Conditions 147 

Hemispatial Neglect 147 

Balint's Syndrome, Simultanagnosia, Dressing Apraxia, 

and Construction Apraxia 148 



The Occipitotemporal Network for Face and Object 
Recognition: Prosopagnosia and Object Agnosia 150 

The Limbic Network for Memory: Amnesias 1 50 

The Prefrontal Network for Attention and Behavior 1 52 

Caring for the Patient with Deficits of Higher 
Cerebral Function 1 53 

Further Readings 1 54 



The cerebral cortex of the human brain contains ~20 
billion neurons spread over an area of 2.5 m 2 .The primary 
sensory areas provide an obligatory portal for the entry of 
sensory information into cortical circuitry, whereas the 
primary motor areas provide final common pathways for 
coordinating complex motor acts. The primary sensory 
and motor areas constitute 10% of the cerebral cortex. 
The rest is subsumed by unimodal, heteromodal, paral- 
imbic, and limbic areas, collectively known as the associa- 
tion cortex (Fig. 15-1). The association cortex mediates 
the integrative processes that subserve cognition, emo- 
tion, and behavior. A systematic testing of these mental 
functions is necessary for the effective clinical assessment 
of the association cortex and its diseases. 

According to current thinking, there are no centers 
for "hearing words," "perceiving space," or "storing mem- 
ories." Cognitive and behavioral functions (domains) are 
coordinated by intersecting large-scale neural networks that 
contain interconnected cortical and subcortical compo- 
nents. The network approach to higher cerebral function 
has at least four implications of clinical relevance: (1) a 
single domain such as language or memory can be dis- 
rupted by damage to any one of several areas, as long as 
these areas belong to the same network; (2) damage 
confined to a single area can give rise to multiple 
deficits, involving the functions of all networks that 
intersect in that region; (3) damage to a network com- 
ponent may give rise to minimal or transient deficits if 



other parts of the network undergo compensatory reor- 
ganization; and (4) individual anatomic sites within a 
network display a relative (but not absolute) specializa- 
tion for different behavioral aspects of the relevant func- 
tion. Five anatomically defined large-scale networks are 
most relevant to clinical practice: a perisylvian network 
for language; a parietofrontal network for spatial cogni- 
tion; an occipitotemporal network for face and object 
recognition; a limbic network for retentive memory; and 
a prefrontal network for attention and behavior. 



THE LEFT PERISYLVIAN NETWORK FOR 
LANGUAGE: APHASIAS AND RELATED 
CONDITIONS 

Language allows the communication and elaboration of 
thoughts and experiences by linking them to arbitrary 
symbols known as words. The neural substrate of lan- 
guage is composed of a distributed network centered in 
the perisylvian region of the left hemisphere. The poste- 
rior pole of this network is located at the temporopari- 
etal junction and includes a region known as Wernicke's 
area. An essential function of Wernicke's area is to trans- 
form sensory inputs into their lexical representations so 
that these can establish the distributed associations that 
give the word its meaning. The anterior pole of the lan- 
guage network is located in the inferior frontal gyrus 



140 





FIGURE 15-1 

Lateral (A) and medial (B) views of the cerebral hemi- 
spheres. The numbers refer to the Brodmann cytoarchitec- 
tonic designations. Area 17 corresponds to the primary 
visual cortex, 41-42 to the primary auditory cortex, 1-3 to 
the primary somatosensory cortex, and 4 to the primary 
motor cortex. The rest of the cerebral cortex contains associ- 
ation areas. AG, angular gyrus; B, Broca's area; CC, corpus 
callosum; CG, cingulate gyrus; DLPFC, dorsolateral pre- 
frontal cortex; FEF, frontal eye fields (premotor cortex); FG, 
fusiform gyrus; IPL, inferior parietal lobule; ITG, inferior tem- 
poral gyrus; LG, lingual gyrus; MPFC, medial prefrontal cor- 
tex; MTG, middle temporal gyrus; OFC, orbitofrontal cortex; 
PHG, parahippocampal gyrus; PPC, posterior parietal cortex; 
PSC, peristriate cortex; SC, striate cortex; SMG, supramar- 
ginal gyrus; SPL, superior parietal lobule; STG, superior tem- 
poral gyrus; STS, superior temporal sulcus; TP, temporopolar 
cortex; W, Wernicke's area. 



and includes a region known as Broca's area. An essential 
function of this area is to transform lexical representa- 
tions into their articulatory sequences so that the words 
can be uttered in the form of spoken language. The 
sequencing function of Broca's area also appears to 
involve the ordering of words into sentences that con- 
tain a meaning-appropriate syntax (grammar). Wernicke's 



and Broca's areas are interconnected with each other 
and with additional perisylvian, temporal, prefrontal, and 
posterior parietal regions, making up a neural network 
subserving the various aspects of language function. 
Damage to any one of these components or to their 
interconnections can give rise to language disturbances 
(aphasia) . Aphasia should be diagnosed only when there 
are deficits in the formal aspects of language such as 
naming, word choice, comprehension, spelling, and syn- 
tax. Dysarthria and mutism do not, by themselves, lead 
to a diagnosis of aphasia. The language network shows a 
left hemisphere dominance pattern in the vast majority 
of the population. In ~90% of right handers and 60% of 
left handers, aphasia occurs only after lesions of the left 
hemisphere. In some individuals no hemispheric domi- 
nance for language can be discerned, and in some others 
(including a small minority of right handers) there is a 
right hemisphere dominance for language. A language 
disturbance occurring after a right hemisphere lesion in 
a right hander is called crossed aphasia. 



CLINICAL EXAMINATION 

The clinical examination of language should include the 
assessment of naming, spontaneous speech, comprehen- 
sion, repetition, reading, and writing. A deficit of naming 
(anomid) is the single most common finding in aphasic 
patients. When asked to name common objects (pencil 
or wristwatch), the patient may fail to come up with the 
appropriate word, may provide a circumlocutious 
description of the object ("the thing for writing"), or 
may come up with the wrong word (paraphasia) . If the 
patient offers an incorrect but legitimate word ("pen" 
for "pencil"), the naming error is known as a semantic 
paraphasia; if the word approximates the correct answer 
but is phonetically inaccurate ("plentil" for "pencil"), it 
is known as a phonemic paraphasia. Asking the patient to 
name body parts, geometric shapes, and component 
parts of objects (lapel of coat, cap of pen) can elicit mild 
forms of anomia in patients who can otherwise name 
common objects. In most anomias, the patient cannot 
retrieve the appropriate name when shown an object 
but can point to the appropriate object when the name 
is provided by the examiner. This is known as a one-way 
(or retrieval-based) naming deficit. A two-way naming 
deficit exists if the patient can neither provide nor rec- 
ognize the correct name, indicating the presence of a 
language comprehension impairment. Spontaneous speech 
is described as "fluent" if it maintains appropriate output 
volume, phrase length, and melody or as "nonfluent" if it 
is sparse, halting, and average utterance length is below 
four words. The examiner should also note if the speech 
is paraphasic or circumlocutious; if it shows a relative 
paucity of substantive nouns and action verbs versus 
function words (prepositions, conjunctions); and if word 



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142 TABLE 15-1 



CLINICAL FEATURES OF APHASIAS AND RELATED CONDITIONS 



COMPREHENSION 



REPETITION OF 
SPOKEN LANGUAGE 



NAMING 



FLUENCY 



Wernicke's 


Impaired 


Impaired 


Impaired 


Preserved or increased 


Broca's 


Preserved (except 
grammar) 


Impaired 


Impaired 


Decreased 


Global 


Impaired 


Impaired 


Impaired 


Decreased 


Conduction 


Preserved 


Impaired 


Impaired 


Preserved 


Nonfluent (motor) transcortical 


Preserved 


Preserved 


Impaired 


Impaired 


Fluent (sensory) transcortical 


Impaired 


Preserved 


Impaired 


Preserved 


Isolation 


Impaired 


Echolalia 


Impaired 


No purposeful speech 


Anomic 


Preserved 


Preserved 


Impaired 


Preserved except for 
word-finding pauses 


Pure word deafness 


Impaired only for 
spoken language 


Impaired 


Preserved 


Preserved 


Pure alexia 


Impaired only for reading 


Preserved 


Preserved 


Preserved 



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order, tenses, suffixes, prefixes, plurals, and possessives are 
appropriate. Comprehension can be tested by assessing the 
patient's ability to follow conversation, by asking yes-no 
questions ("Can a dog fly?", "Does it snow in sum- 
mer?") or asking the patient to point to appropriate 
objects ("Where is the source of illumination in this 
room?"). Statements with embedded clauses or passive 
voice construction ("If a tiger is eaten by a lion, which 
animal stays alive?") help to assess the ability to compre- 
hend complex syntactic structure. Commands to close 
or open the eyes, stand up, sit down, or roll over should 
not be used to assess overall comprehension since appro- 
priate responses aimed at such axial movements can be 
preserved in patients who otherwise have profound 
comprehension deficits. 

Repetition is assessed by asking the patient to repeat 
single words, short sentences, or strings of words such as 
"No ifs, ands, or buts." The testing of repetition with 
tongue-twisters such as "hippopotamus" or "Irish con- 
stabulary" provides a better assessment of dysarthria and 
palilalia than aphasia. Aphasic patients may have little 
difficulty with tongue-twisters but have a particularly 
hard time repeating a string of function words. It is 
important to make sure that the number of words does 
not exceed the patient's attention span. Otherwise, the 
failure of repetition becomes a reflection of the nar- 
rowed attention span rather than an indication of an 
aphasic deficit. Reading should be assessed for deficits in 
reading aloud as well as comprehension. Writing is 
assessed for spelling errors, word order, and grammar. 
Alexia describes an inability to either read aloud or 
comprehend single words and simple sentences; agraphia 
(or dysgraphia) is used to describe an acquired deficit in 
the spelling or grammar of written language. 

The correspondence between individual deficits of 
language function and lesion location does not display a 



rigid one-to-one relationship and should be conceptual- 
ized within the context of the distributed network model. 
Nonetheless, the classification of aphasias of acute onset 
into specific clinical syndromes helps to determine the 
most likely anatomic distribution of the underlying 
neurologic disease and has implications for etiology 
and prognosis (Table 15-1). The syndromes listed in 
Table 15-1 are most applicable to aphasias caused by 
cerebrovascular accidents (CVA). They can be divided 
into "central" syndromes, which result from damage to 
the two epicenters of the language network (Broca's and 
Wernicke's areas), and "disconnection" syndromes, which 
arise from lesions that interrupt the functional connec- 
tivity of these centers with each other and with the other 
components of the language network. The syndromes 
outlined below are idealizations; pure syndromes occur 
rarely. 

Wernicke's Aphasia 

Comprehension is impaired for spoken and written lan- 
guage. Language output is fluent but is highly paraphasic 
and circumlocutious.The tendency for paraphasic errors 
may be so pronounced that it leads to strings of neolo- 
gisms, which form the basis of what is known as "jargon 
aphasia." Speech contains large numbers of function 
words (e.g., prepositions, conjunctions) but few substan- 
tive nouns or verbs that refer to specific actions. The 
output is therefore voluminous but uninformative. For 
example, a patient attempts to describe how his wife 
accidentally threw away something important, perhaps 
his dentures: "We don't need it anymore, she says. And 
with it when that was downstairs was my teeth-tick ... a 
. . . den . . . dentith . . . my dentist. And they happened to 
be in that bag . . . see? How could this have happened? 
How could a thing like this happen ... So she says we 



won't need it anymore ... I didn't think we'd use it. And 
now if I have any problems anybody coming a month 
from now, 4 months from now, or 6 months from now, I 
have a new dentist. Where my two . . . two little pieces 
of dentist that I use . . . that I ... all gone. If she throws 
the whole thing away . . . visit some friends of hers and 
she can't throw them away." 

Gestures and pantomime do not improve communi- 
cation. The patient does not seem to realize that his or 
her language is incomprehensible and may appear angry 
and impatient when the examiner fails to decipher the 
meaning of a severely paraphasic statement. In some 
patients this type of aphasia can be associated with 
severe agitation and paranoid behaviors. One area of 
comprehension that may be preserved is the ability to 
follow commands aimed at axial musculature. The disso- 
ciation between the failure to understand simple ques- 
tions ("What is your name?") in a patient who rapidly 
closes his or her eyes, sits up, or rolls over when asked to 
do so is characteristic of Wernicke's aphasia and helps to 
differentiate it from deafness, psychiatric disease, or 
malingering. Patients with Wernicke's aphasia cannot 
express their thoughts in meaning-appropriate words 
and cannot decode the meaning of words in any modal- 
ity of input. This aphasia therefore has expressive as well 
as receptive components. Repetition, naming, reading, 
and writing are also impaired. 

The lesion site most commonly associated with Wer- 
nicke's aphasia is the posterior portion of the language net- 
work and tends to involve at least parts of Wernicke's area. 
An embolus to the inferior division of the middle cerebral 
artery, and to the posterior temporal or angular branches in 
particular, is the most common etiology (Chap. 21). Intrac- 
erebral hemorrhage, severe head trauma, or neoplasm are 
other causes. A coexisting right hemi- or superior quadran- 
tanopia is common, and mild right nasolabial flattening 
may be found, but otherwise the examination is often 
unrevealing. The paraphasic, neologistic speech in an agi- 
tated patient with an otherwise unremarkable neurologic 
examination may lead to the suspicion of a primary psychi- 
atric disorder such as schizophrenia or mania, but the other 
components characteristic of acquired aphasia and the 
absence of prior psychiatric disease usually settle the issue. 
Some patients with Wernicke's aphasia due to intracerebral 
hemorrhage or head trauma may improve as the hemor- 
rhage or the injury heals. In most other patients, prognosis 
for recovery is guarded. 

Broca's Aphasia 

Speech is nonfluent, labored, interrupted by many 
word-finding pauses, and usually dysarthric. It is impov- 
erished in function words but enriched in meaning- 
appropriate nouns and verbs. Abnormal word order and 
the inappropriate deployment of bound morphemes (word 
endings used to denote tenses, possessives, or plurals) 



lead to a characteristic agrammatism. Speech is tele- 
graphic and pithy but quite informative. In the follow- 
ing passage, a patient with Broca's aphasia describes his 
medical history: "I see . . . the dotor, dotor sent me . . . 
Bosson. Go to hospital. Dotor . . . kept me beside. Two, 
tee days, doctor send me home." 

Output may be reduced to a grunt or single word 
("yes" or "no"), which is emitted with different intona- 
tions in an attempt to express approval or disapproval. In 
addition to fluency, naming and repetition are also 
impaired. Comprehension of spoken language is intact, 
except for syntactically difficult sentences with passive 
voice structure or embedded clauses. Reading compre- 
hension is also preserved, with the occasional exception of 
a specific inability to read small grammatical words such as 
conjunctions and pronouns. The last two features indicate 
that Broca's aphasia is not just an "expressive" or "motor" 
disorder and that it may also involve a comprehension 
deficit for function words and syntax. Patients with Broca's 
aphasia can be tearful, easily frustrated, and profoundly 
depressed. Insight into their condition is preserved, in con- 
trast to Wernicke's aphasia. Even when spontaneous speech 
is severely dysarthric, the patient may be able to display a 
relatively normal articulation of words when singing. This 
dissociation has been used to develop specific therapeutic 
approaches (melodic intonation therapy) for Broca's apha- 
sia. Additional neurologic deficits usually include right 
facial weakness, hemiparesis or hemiplegia, and a buccofa- 
cial apraxia characterized by an inability to carry out 
motor commands involving oropharyngeal and facial mus- 
culature (e.g., patients are unable to demonstrate how to 
blow out a match or suck through a straw). Visual fields are 
intact. The cause is most often infarction of Broca's area 
(the inferior frontal convolution; "B" in Fig. 15-1) and sur- 
rounding anterior perisylvian and insular cortex, due to 
occlusion of the superior division of the middle cerebral 
artery (Chap. 21). Mass lesions including tumor, intracere- 
bral hemorrhage, or abscess may also be responsible. Small 
lesions confined to the posterior part of Broca's area may 
lead to a nonaphasic and often reversible deficit of speech 
articulation, usually accompanied by mild right facial 
weakness. When the cause of Broca's aphasia is stroke, 
recovery of language function generally peaks within 2—6 
months, after which time further progress is limited. 

Global Aphasia 

Speech output is nonfluent, and comprehension of spo- 
ken language is severely impaired. Naming, repetition, 
reading, and writing are also impaired. This syndrome 
represents the combined dysfunction of Broca's and 
Wernicke's areas and usually results from strokes that 
involve the entire middle cerebral artery distribution in 
the left hemisphere. Most patients are initially mute or say 
a few words, such as "hi" or "yes." Related signs include 
right hemiplegia, hemisensory loss, and homonymous 



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hemianopia. Occasionally, a patient with a lesion in Wer- 
nicke's area will present with a global aphasia that soon 
resolves into Wernicke's aphasia. 

Conduction Aphasia 

Speech output is fluent but paraphasic, comprehension 
of spoken language is intact, and repetition is severely 
impaired. Naming and writing are also impaired. Read- 
ing aloud is impaired, but reading comprehension is pre- 
served. The lesion sites spare Broca's and Wernicke's areas 
but may induce a functional disconnection between the 
two so that lexical representations formed in Wernicke's 
area and adjacent regions cannot be conveyed to Broca's 
area for assembly into corresponding articulatory pat- 
terns. Occasionally, a Wernicke's area lesion gives rise to 
a transient Wernicke's aphasia that rapidly resolves into a 
conduction aphasia. The paraphasic output in conduc- 
tion aphasia interferes with the ability to express mean- 
ing, but this deficit is not nearly as severe as the one dis- 
played by patients with Wernicke's aphasia. Associated 
neurologic signs in conduction aphasia vary according 
to the primary lesion site. 



pathologic function of the language network when it is 
isolated from other regions of the brain. Broca's and 
Wernicke's areas tend to be spared, but there is damage 
to the surrounding frontal, parietal, and temporal cortex. 
Lesions are patchy and can be associated with anoxia, 
carbon monoxide poisoning, or complete watershed 
zone infarctions. 

Anomic Aphasia 

This form of aphasia may be considered the "minimal 
dysfunction" syndrome of the language network. Articu- 
lation, comprehension, and repetition are intact, but 
confrontation naming, word finding, and spelling are 
impaired. Speech is enriched in function words but 
impoverished in substantive nouns and verbs denoting 
specific actions. Language output is fluent but parapha- 
sic, circumlocutious, and uninformative. The lesion sites 
can be anywhere within the left hemisphere language 
network, including the middle and inferior temporal 
gyri. Anomic aphasia is the single most common language dis- 
turbance seen in head trauma, metabolic encephalopathy, and 
Alzheimer's disease. 



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Nonfluent Transcortical Aphasia 
(Transcortical Motor Aphasia) 

The features are similar to Broca's aphasia, but repetition 
is intact and agrammatism may be less pronounced. The 
neurologic examination may be otherwise intact, but a 
right hemiparesis can also exist. The lesion site disconnects 
the intact language network from prefrontal areas of the 
brain and usually involves the anterior watershed zone 
between anterior and middle cerebral artery territories 
or the supplementary motor cortex in the territory of the 
anterior cerebral artery. 

Fluent Transcortical Aphasia 
(Transcortical Sensory Aphasia) 

Clinical features are similar to those of Wernicke's apha- 
sia, but repetition is intact. The lesion site disconnects the 
intact core of the language network from other tem- 
poroparietal association areas. Associated neurologic find- 
ings may include hemianopia. Cerebrovascular lesions 
(e.g., infarctions in the posterior watershed zone) or neo- 
plasms that involve the temporoparietal cortex posterior 
to Wernicke's area are the most common causes. 



Pure Word Deafness 

The most common causes are either bilateral or left- 
sided middle cerebral artery strokes affecting the supe- 
rior temporal gyrus. The net effect of the underlying 
lesion is to interrupt the flow of information from the 
unimodal auditory association cortex to Wernicke's area. 
Patients have no difficulty understanding written lan- 
guage and can express themselves well in spoken or 
written language. They have no difficulty interpreting 
and reacting to environmental sounds since primary 
auditory cortex and subcortical auditory relays are 
intact. Since auditory information cannot be conveyed 
to the language network, however, it cannot be decoded 
into lexical representations and the patient reacts to 
speech as if it were in an alien tongue that cannot be 
deciphered. Patients cannot repeat spoken language but 
have no difficulty naming objects. In time, patients with 
pure word deafness teach themselves lip reading and 
may appear to have improved. There may be no addi- 
tional neurologic findings, but agitated paranoid reac- 
tions are frequent in the acute stages. Cerebrovascular 
lesions are the most frequent cause. 



Isolation Aphasia 

This rare syndrome represents a combination of the two 
transcortical aphasias. Comprehension is severely impaired, 
and there is no purposeful speech output. The patient 
may parrot fragments of heard conversations (echolalia), 
indicating that the neural mechanisms for repetition are 
at least partially intact. This condition represents the 



Pure Alexia without Agraphia 

This is the visual equivalent of pure word deafness. The 
lesions (usually a combination of damage to the left 
occipital cortex and to a posterior sector of the corpus 
callosum — the splenium) interrupt the flow of visual 
input into the language network. There is usually a right 
hemianopia, but the core language network remains 



unaffected. The patient can understand and produce 
spoken language, name objects in the left visual hemi- 
field, repeat, and write. However, the patient acts as if 
illiterate when asked to read even the simplest sentence 
because the visual information from the written words 
(presented to the intact left visual hemifield) cannot 
reach the language network. Objects in the left hemi- 
field may be named accurately because they activate 
nonvisual associations in the right hemisphere, which, in 
turn, can access the language network through transcal- 
losal pathways anterior to the splenium. Patients with 
this syndrome may also lose the ability to name colors, 
although they can match colors. This is known as a color 
anomia. The most common etiology of pure alexia is a 
vascular lesion in the territory of the posterior cerebral 
artery or an infiltrating neoplasm in the left occipital 
cortex that involves the optic radiations as well as the 
crossing fibers of the splenium. Since the posterior cere- 
bral artery also supplies medial temporal components of 
the limbic system, the patient with pure alexia may also 
experience an amnesia, but this is usually transient 
because the limbic lesion is unilateral. 

Aphemia 

There is an acute onset of severely impaired fluency 
(often mutism), which cannot be accounted for by cor- 
ticobulbar, cerebellar, or extrapyramidal dysfunction. 
Recovery is the rule and involves an intermediate stage 
of hoarse whispering. Writing, reading, and comprehen- 
sion are intact, so this is not a true aphasic syndrome. 
Partial lesions of Broca's area or subcortical lesions that 
undercut its connections with other parts of the brain 
may be present. Occasionally, the lesion site is on the 
medial aspects of the frontal lobes and may involve the 
supplementary motor cortex of the left hemisphere. 

Apraxia 

This generic term designates a complex motor deficit 
that cannot be attributed to pyramidal, extrapyramidal, 
cerebellar, or sensory dysfunction and that does not 
arise from the patient's failure to understand the nature 
of the task. The form that is most frequently encoun- 
tered in clinical practice is known as ideomotor apraxia. 
Commands to perform a specific motor act ("cough," 
"blow out a match") or to pantomime the use of a com- 
mon tool (a comb, hammer, straw, or toothbrush) in the 
absence of the real object cannot be followed. The 
patient's ability to comprehend the command is ascer- 
tained by demonstrating multiple movements and estab- 
lishing that the correct one can be recognized. Some 
patients with this type of apraxia can imitate the appro- 
priate movement (when it is demonstrated by the 
examiner) and show no impairment when handed the 
real object, indicating that the sensorimotor mechanisms 



necessary for the movement are intact. Some forms of 
ideomotor apraxia represent a disconnection of the lan- 
guage network from pyramidal motor systems: commands 
to execute complex movements are understood but can- 
not be conveyed to the appropriate motor areas, even 
though the relevant motor mechanisms are intact. Bucco- 
facial apraxia involves apraxic deficits in movements of 
the face and mouth. Limb apraxia encompasses apraxic 
deficits in movements of the arms and legs. Ideomotor 
apraxia is almost always caused by lesions in the left 
hemisphere and is commonly associated with aphasic 
syndromes, especially Broca's aphasia and conduction 
aphasia. Its presence cannot be ascertained in patients 
with language comprehension deficits. The ability to 
follow commands aimed at axial musculature ("close 
the eyes," "stand up") is subserved by different pathways 
and may be intact in otherwise severely aphasic and 
apraxic patients. Patients -with lesions of the anterior 
corpus callosum can display a special type of ideomotor 
apraxia confined to the left side of the body. Since the 
handling of real objects is not impaired, ideomotor 
apraxia, by itself, causes no major limitation of daily liv- 
ing activities. 

Ideational apraxia refers to a deficit in the execution of 
a goal-directed sequence of movements in patients who 
have no difficulty executing the individual components 
of the sequence. For example, when asked to pick up a 
pen and write, the sequence of uncapping the pen, plac- 
ing the cap at the opposite end, turning the point toward 
the writing surface, and writing may be disrupted, and 
the patient may be seen trying to write with the wrong 
end of the pen or even with the removed cap. These 
motor sequencing problems are usually seen in the con- 
text of confusional states and dementias rather than focal 
lesions associated with aphasic conditions. Limb-kinetic 
apraxia involves a clumsiness in the actual use of tools that 
cannot be attributed to sensory, pyramidal, extrapyramidal, 
or cerebellar dysfunction. This condition can emerge in 
the context of focal premotor cortex lesions or corticobasal 
ganglionic degeneration. 

Gerstmann's Syndrome 

The combination of acalculia (impairment of simple arith- 
metic), dysgraphia (impaired writing), finger anomia (an 
inability to name individual fingers such as the index or 
thumb), and right-left confusion (an inability to tell whether 
a hand, foot, or arm of the patient or examiner is on the 
right or left side of the body) is known as Gerstmann's 
syndrome. In making this diagnosis it is important to 
establish that the finger and left-right naming deficits 
are not part of a more generalized anomia and that the 
patient is not otherwise aphasic. When Gerstmann's syn- 
drome is seen in isolation, it is commonly associated 
with damage to the inferior parietal lobule (especially 
the angular gyrus) in the left hemisphere. 



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146 Aprosodia 

Variations of melodic stress and intonation influence the 
meaning and impact of spoken language. For example, 
the two statements "He is clever." and "He is clever?" con- 
tain an identical word choice and syntax but convey 
vastly different messages because of differences in the 
intonation and stress with which the statements are 
uttered. This aspect of language is known as prosody. 
Damage to perisylvian areas in the right hemisphere can 
interfere with speech prosody and can lead to syndromes 
of aprosodia. Damage to right hemisphere regions corre- 
sponding to Wernicke's area can selectively impair decoding 
of speech prosody, whereas damage to right hemisphere 
regions corresponding to Broca's area yields a greater impair- 
ment in the ability to introduce meaning-appropriate 
~ prosody into spoken language. The latter deficit is the 
3 most common type of aprosodia identified in clinical 
^ practice — the patient produces grammatically correct lan- 
^ guage with accurate word choice but the statements are 
Pd 1 uttered in a monotone that interferes with the ability to 
ST convey the intended stress and affect. Patients with this 
o' type of aprosodia give the mistaken impression of being 
00 depressed or indifferent. 



Subcortical Aphasia 

Damage to subcortical components of the language net- 
work (e.g., the striatum and thalamus of the left hemi- 
sphere) can also lead to aphasia. The resulting syndromes 
contain combinations of deficits in the various aspects of 
language but rarely fit the specific patterns described in 
Table 15-1. In a patient with a CVA, an anomic aphasia 
accompanied by dysarthria or a fluent aphasia with 
hemiparesis should raise the suspicion of a subcortical 
lesion site. 

Progressive Aphasias 

In clinical practice, acquired aphasias are most com- 
monly encountered in one of two contexts: CVAs and 
degenerative diseases. Aphasias caused by CVAs start 
suddenly and display maximal deficits at the onset. The 
underlying lesion is relatively circumscribed and associ- 
ated with a total loss of neural function at the lesion site. 
These are the "classic" aphasias described earlier where rel- 
atively reproducible relationships between lesion site and 
aphasia pattern can be discerned. Aphasias caused by 
neurodegenerative diseases have an insidious onset and 
relentless progression so that the symptomatology changes 
over time. Since the neuronal loss within the areas 
encompassed by the neurodegeneration is partial and 
since it tends to include multiple components of the 
language network, distinctive clinical patterns and clinico- 
anatomic correlations are less obvious. 

Dementia is a generic term used to designate a neu- 
rodegenerative disease that impairs intellect and behavior 



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to the point where customary daily living activities 
become compromised (Chap. 23) . Alzheimer's disease is 
the single most common cause of dementia. The neu- 
ropathology of Alzheimer's disease causes the earliest and 
most profound neuronal loss in memory-related parts of 
the brain such as the entorhinal cortex and the hip- 
pocampus. This is why progressive forgetfulness for 
recent events and experiences is the cardinal feature of 
Alzheimer's disease. In time, the neuronal pathology in 
Alzheimer's disease spreads to the language network and a 
progressive aphasia, usually of the anomic type, becomes 
added to the progressive amnesia. There are other pat- 
terns of dementia, however, where neurodegeneration 
initially targets the language rather than memory net- 
work of the brain, leading to the emergence of a pro- 
gressive aphasia that becomes the most prominent aspect 
of the clinical picture during the initial phases of the 
disease. Primary progressive aphasia (PPA) is the most 
widely recognized syndrome with this pattern of selec- 
tive language impairment. 

^H Clinical Presentation and Diagnosis of PPA 

The patient with PPA comes to medical attention 
because of word-finding difficulties, abnormal speech 
patterns, and spelling errors of recent onset. PPA is diag- 
nosed when other mental faculties such as memory for 
daily events, visuospatial skills (assessed by tests of draw- 
ing and face recognition), and comportment (assessed by 
history obtained from a third party) remain relatively 
intact; when language is the major area of dysfunction 
for the first few years of the disease; and when structural 
brain imaging does not reveal a specific lesion, other than 
atrophy, to account for the language deficit. Impairments 
in other cognitive functions may also emerge, but the 
language dysfunction remains the most salient feature 
and deteriorates most rapidly throughout the illness. 

^H Language in PPA 

The language impairment in PPA varies from patient to 
patient. Some patients cannot find the right words to 
express thoughts; others cannot understand the meaning 
of heard or seen words; still others cannot name objects 
in the environment. The language impairment can be 
fluent (that is, with normal articulation, flow, and num- 
ber of words per utterance) or nonfluent. The single 
most common sign of primary progressive aphasia is 
anomia, manifested by an inability to come up with the 
right word during conversation and/or an inability to 
name objects shown by the examiner. Many patients 
remain in an anomic phase through most of the disease 
and experience a gradual intensification of word-finding 
deficits to the point of near-mutism. Others, however, 
proceed to develop distinct forms of agrammatism 
and/or word comprehension deficits. The agrammatism 
consists of inappropriate word order and misuse of small 



grammatical words. One patient, for example, sent the 
following e-mail to her daughter: "I will come my 
house in your car and drive my car into Chicago. . . .You 
will back get your car and my car park in my driveway. 
Love, Mom." Comprehension deficits, if present, start 
with an occasional inability to understand single low- 
frequency words and gradually progress to encompass 
the comprehension of conversational speech. 

The impairments of syntax, comprehension, naming, 
or writing in PPA are no different from those seen in 
aphasias of cerebrovascular causes. However, they form 
slightly different patterns. According to a classification 
proposed by Gorno-Tempini and colleagues, three vari- 
ants of PPA can be recognized: an agrammatical variant 
characterized by poor fluency and impaired syntax, a 
semantic variant characterized by preserved fluency and 
syntax but poor single word comprehension, and a 
logopenic variant characterized by preserved syntax and 
comprehension but frequent word-finding pauses dur- 
ing spontaneous speech. The agrammatical variant is also 
known as progressive nonfluent aphasia and displays simi- 
larities to Broca's aphasia. However, dysarthria is usually 
absent. The semantic variant of PPA is also known as 
semantic dementia and displays similarities to Wernicke's 
aphasia, but the comprehension difficulty tends to be 
milder. The most obvious difference between aphasias 
caused by CVA and those caused by neurodegenerative 
disease is the post-stroke improvement in CVA-related 
aphasias, leading to a progressive crystallization of the 
subtypes listed in Table 15-1, versus the gradual deterio- 
ration that leads to a loss of syndromic specificity as the 
disease progresses. 

^H Pathophysiology 

Patients with PPA display progressive atrophy (indica- 
tive of neuronal loss), electroencephalographic slowing, 
decreased blood flow (measured by single photon emis- 
sion CT) and decreased glucose utilization (measured 
by positron emission tomography) that are most pro- 
nounced within the language network of the brain. The 
abnormalities may remain confined to left hemisphere 
perisylvian and anterior temporal cortices for many 
years. The clinical focality of primary progressive aphasia 
is thus matched by the anatomic selectivity of the under- 
lying pathologic process. 

The three variants display overlapping distributions of 
neuronal loss but the agrammatical variant is most 
closely associated with atrophy in the anterior parts of 
the language network (where Broca's area is located), the 
semantic variant with atrophy in the temporal compo- 
nents of the language network, and the logopenic vari- 
ant with atrophy in the temporoparietal component of 
the language network. The relationship between poor 
language comprehension and damage to Wernicke's area, 
which is a feature of CVA-related aphasias, is not present 
in PPA. Instead, poor comprehension is most closely 



associated with neuronal loss in the lateral and anterior 147 
temporal cortex. 



^H Neuropathology 

Approximately 30% of patients have shown the micro- 
scopic pathology of Alzheimer's disease, presumably with 
an atypical distribution of lesions. In the majority of 
cases, the neuropathology falls within the family of fron- 
totemporal lobar degenerations (FTLD) and displays 
various combinations of focal neuronal loss, gliosis, tau- 
positive inclusions, Pick bodies, and tau-negative ubiqui- 
tin inclusions (Chap. 23). Familial forms of PPA with 
tau-negative ubiquinated inclusions have recently been 
linked to mutations of the progranulin gene on chromo- 
some 17. Apolipoprotein E and prion protein genotyp- 
ing has shown differences between patients with typical 
clinical patterns of Alzheimer's disease and those with a 
diagnosis of PPA. The intriguing possibility has been 
raised that a personal or family history of dyslexia may 
be a risk factor for primary progressive aphasia, at least 
in some patients, suggesting that this disease may arise 
on a background of genetic or developmental vulnera- 
bility affecting language-related areas of the brain. 



THE PARIETOFRONTAL NETWORK FOR 
SPATIAL ORIENTATION: NEGLECT AND 
RELATED CONDITIONS 

HEMISPATIAL NEGLECT 

Adaptive orientation to significant events within the 
extrapersonal space is subserved by a large-scale network 
containing three major cortical components. The cingulate 
cortex provides access to a limbic-motivational mapping 
of the extrapersonal space, the posterior parietal cortex to a 
sensorimotor representation of salient extrapersonal 
events, and the frontal eye fields to motor strategies for 
attentional behaviors (Fig. 15-2). Subcortical compo- 
nents of this network include the striatum and the thala- 
mus. Contralesional hemispatial neglect represents one 
outcome of damage to any of the cortical or subcortical 
components of this network. The traditional view that 
hemispatial neglect always denotes a parietal lobe lesion is inac- 
curate. In keeping with this anatomic organization, the 
clinical manifestations of neglect display three behavioral 
components: sensory events (or their mental representa- 
tions) within the neglected hemispace have a lesser impact 
on overall awareness; there is a paucity of exploratory and 
orienting acts directed toward the neglected hemispace; 
and the patient behaves as if the neglected hemispace 
was motivationally devalued. 

According to one model of spatial cognition, the 
right hemisphere directs attention within the entire 
extrapersonal space, whereas the left hemisphere directs 
attention mostly within the contralateral right hemispace. 



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FIGURE 15-2 

Functional magnetic resonance imaging of language 
and spatial attention in neurologically intact subjects. 

The dark areas show regions of task-related significant 
activation. (A) The subjects were asked to determine if two 
words were synonymous. This language task led to the 
simultaneous activation of the two epicenters of the lan- 
guage network, Broca's area (B) and Wernicke's area (W). 
The activations are exclusively in the left hemisphere. (S) 
The subjects were asked to shift spatial attention to a 
peripheral target. This task led to the simultaneous activa- 
tion of the three epicenters of the attentional network, the 
posterior parietal cortex (P), the frontal eye fields (F), and 
the cingulate gyrus (CG). The activations are predominantly 
in the right hemisphere. (Courtesy of Darren Gitelman, MD; 
with permission.) 



Consequently, unilateral left hemisphere lesions do not 
give rise to much contralesional neglect since the global 
attentional mechanisms of the right hemisphere can 
compensate for the loss of the contmhtemlly directed 
attentional functions of the left hemisphere. Unilateral 
right hemisphere lesions, however, give rise to severe 
contralesional left hemispatial neglect because the unaf- 
fected left hemisphere does not contain ipsilateral atten- 
tional mechanisms. This model is consistent with clinical 
experience, which shows that contralesional neglect is 
more common, severe, and lasting after damage to the 
right hemisphere than after damage to the left hemi- 
sphere. Severe neglect for the right hemispace is rare, 
even in left handers with left hemisphere lesions. 

Patients with severe neglect may fail to dress, shave, or 
groom the left side of the body; may fail to eat food 



placed on the left side of the tray; and may fail to read 
the left half of sentences. When the examiner draws a 
large circle [12—15 cm (5—6 in.) in diameter] and asks 
the patient to place the numbers 1—12 as if the circle 
represented the face of a clock, there is a tendency to 
crowd the numbers on the right side and leave the left 
side empty. When asked to copy a simple line drawing, 
the patient fails to copy detail on the left; and when 
asked to write, there is a tendency to leave an unusually 
wide margin on the left. 

Two bedside tests that are useful in assessing neglect 
are simultaneous bilateral stimulation and visual target cancel- 
lation. In the former, the examiner provides either uni- 
lateral or simultaneous bilateral stimulation in the visual, 
auditory, and tactile modalities. Following right hemi- 
sphere injury, patients who have no difficulty detecting 
unilateral stimuli on either side experience the bilater- 
ally presented stimulus as coming only from the right. 
This phenomenon is known as extinction and is a mani- 
festation of the sensory-representational aspect of 
hemispatial neglect. In the target detection task, targets 
(e.g., As) are interspersed with foils (e.g., other letters 
of the alphabet) on a 21.5 X 28.0 cm (8.5 X 11 in.) 
sheet of paper and the patient is asked to circle all the 
targets. A failure to detect targets on the left is a manifes- 
tation of the exploratory deficit in hemispatial neglect 
(Fig. 15-3.4). Hemianopia, by itself, does not interfere 
with performance in this task since the patient is free to 
turn the head and eyes to the left. The normal tendency 
in target detection tasks is to start from the left upper 
quadrant and move systematically in horizontal or ver- 
tical sweeps. Some patients show a tendency to start the 
process from the right and proceed in a haphazard fashion. 
This represents a subtle manifestation of left neglect, 
even if the patient eventually manages to detect all the 
appropriate targets. Some patients with neglect may also 
deny the existence of hemiparesis and may even deny 
ownership of the paralyzed limb, a condition known as 
anosognosia. 

Cerebrovascular lesions and neoplasms in the right 
hemisphere are the most common causes of hemispatial 
neglect. Depending on the site of the lesion, the patient 
with neglect may also have hemiparesis, hemihypesthesia, 
and hemianopia on the left, but these are not invariant 
findings. The majority of patients display considerable 
improvement of hemispatial neglect, usually -within the 
first several weeks. 

BALINT'S syndrome, simultanagnosia, 

DRESSING APRAXIA, AND CONSTRUCTION 
APRAXIA 

Bilateral involvement of the network for spatial attention, 
especially its parietal components, leads to a state of severe 
spatial disorientation known as Balint's syndrome. Balint's 
syndrome involves deficits in the orderly visuomotor 



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FIGURE 15-3 

Evidence of left hemispatial 
neglect and simultanagnosia. 

A. A 47-year-old man with a 
large frontoparietal lesion in the 
right hemisphere was asked to 
circle all the As. Only targets on 
the right are circled. This is a 
manifestation of left hemispatial 
neglect. B. A 70-year-old woman 
with a 2-year history of degener- 
ative dementia was able to circle 
most of the small targets but 
ignored the larger ones. This is a 
manifestation of simultanagnosia. 



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scanning of the environment (oculomotor apraxia) and in 
accurate manual reaching toward visual targets (optic ataxia). 
The third and most dramatic component of Balint's syn- 
drome is known as simultanagnosia and reflects an inabil- 
ity to integrate visual information in the center of gaze 
with more peripheral information. The patient gets 
stuck on the detail that falls in the center of gaze with- 
out attempting to scan the visual environment for addi- 
tional information. The patient with simultanagnosia 
"misses the forest for the trees." Complex visual scenes 
cannot be grasped in their entirety, leading to severe 
limitations in the visual identification of objects and 
scenes. For example, a patient who is shown a table 
lamp and asked to name the object may look at its 
circular base and call it an ash tray. Some patients with 



simultanagnosia report that objects they look at may 
suddenly vanish, probably indicating an inability to look 
back at the original point of gaze after brief saccadic 
displacements. Movement and distracting stimuli greatly 
exacerbate the difficulties of visual perception. Simul- 
tanagnosia can sometimes occur without the other two 
components of Balint's syndrome. 

A modification of the letter cancellation task described 
above can be used for the bedside diagnosis of simul- 
tanagnosia. In this modification, some of the targets 
(e.g., As) are made to be much larger than the others 
[7.5—10 cm vs 2.5 cm (3—4 in. vs 1 in.) in height], and all 
targets are embedded among foils. Patients with simul- 
tanagnosia display a counterintuitive but characteristic 
tendency to miss the larger targets (Fig. 15-3jB). This 



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occurs because the information needed for the identifi- 
cation of the larger targets cannot be confined to the 
immediate line of gaze and requires the integration of 
visual information across a more extensive field of view. 
The greater difficulty in the detection of the larger tar- 
gets also indicates that poor acuity is not responsible for 
the impairment of visual function and that the problem 
is central rather than peripheral. Balint's syndrome 
results from bilateral dorsal parietal lesions; common set- 
tings include watershed infarction between the middle 
and posterior cerebral artery territories, hypoglycemia, 
sagittal sinus thrombosis, or atypical forms of Alzheimer's 
disease. In patients with Balint's syndrome due to stroke, 
bilateral visual field defects (usually inferior quadran- 
tanopias) are common. 

Another manifestation of bilateral (or right-sided) 
dorsal parietal lobe lesions is dressing apraxia. The patient 
with this condition is unable to align the body axis with 
the axis of the garment and can be seen struggling as he 
or she holds a coat from its bottom or extends his or her 
arm into a fold of the garment rather than into its 
sleeve. Lesions that involve the posterior parietal cortex 
also lead to severe difficulties in copying simple line 
drawings. This is known as a construction apraxia and is 
much more severe if the lesion is in the right hemi- 
sphere. In some patients with right hemisphere lesions, 
the drawing difficulties are confined to the left side of 
the figure and represent a manifestation of hemispatial 
neglect; in others, there is a more universal deficit in 
reproducing contours and three-dimensional perspec- 
tive. Dressing apraxia and construction apraxia represent 
special instances of a more general disturbance in spatial 
orientation. 



THE OCCIPITOTEMPORAL NETWORK 
FOR FACE AND OBJECT RECOGNITION: 
PROSOPAGNOSIA AND OBJECT 
AGNOSIA 

Perceptual information about faces and objects is ini- 
tially encoded in primary (striate) visual cortex and 
adjacent (upstream) peristriate visual association areas. 
This information is subsequently relayed first to the 
downstream visual association areas of occipitotemporal 
cortex and then to other heteromodal and paralimbic 
areas of the cerebral cortex. Bilateral lesions in the 
fusiform and lingual gyri of the occipitotemporal cortex 
disrupt this process and interfere with the ability of other- 
wise intact perceptual information to activate the distrib- 
uted multimodal associations that lead to the recognition 
of faces and objects. The resultant face and object recog- 
nition deficits are known as prosopagnosia and visual object 
agnosia. 

The patient with prosopagnosia cannot recognize famil- 
iar faces, including, sometimes, the reflection of his or 



her own face in the mirror. This is not a perceptual 
deficit since prosopagnosic patients can easily tell if two 
faces are identical or not. Furthermore, a prosopagnosic 
patient who cannot recognize a familiar face by visual 
inspection alone can use auditory cues to reach appro- 
priate recognition if allowed to listen to the person's 
voice. The deficit in prosopagnosia is therefore modality- 
specific and reflects the existence of a lesion that prevents 
the activation of otherwise intact multimodal templates 
by relevant visual input. Damasio has pointed out that 
the deficit in prosopagnosia is not limited to the recog- 
nition of faces but that it can also extend to the recogni- 
tion of individual members of larger generic object 
groups. For example, prosopagnosic patients characteris- 
tically have no difficulty with the generic identification 
of a face as a face or of a car as a car, but they cannot 
recognize the identity of an individual face or the make 
of an individual car. This reflects a visual recognition 
deficit for proprietary features that characterize individ- 
ual members of an object class. When recognition prob- 
lems become more generalized and extend to the generic 
identification of common objects, the condition is known 
as visual object agnosia. In contrast to prosopagnosic 
patients, those with object agnosia cannot recognize a face 
as a face or a car as a car. 

It is important to distinguish visual object agnosia 
from anomia. The patient with anomia cannot name the 
object but can describe its use. In contrast, the patient 
with visual agnosia is unable either to name a visually 
presented object or to describe its use. The characteristic 
lesions in prosopagnosia and visual object agnosia consist 
of bilateral infarctions in the territory of the posterior 
cerebral arteries. Associated deficits can include visual 
field defects (especially superior quadrantanopias) or a 
centrally based color blindness known as achromatopsia. 
Rarely, the responsible lesion is unilateral. In such cases, 
prosopagnosia is associated with lesions in the right 
hemisphere and object agnosia with lesions in the left. 



THE LIMBIC NETWORK FOR MEMORY: 
AMNESIAS 

Limbic and paralimbic areas (such as the hippocampus, 
amygdala, and entorhinal cortex), the anterior and 
medial nuclei of the thalamus, the medial and basal parts 
of the striatum, and the hypothalamus collectively con- 
stitute a distributed network known as the limbic system. 
The behavioral affiliations of this network include the 
coordination of emotion, motivation, autonomic tone, 
and endocrine function. An additional area of specializa- 
tion for the limbic network, and the one -which is of 
most relevance to clinical practice, is that of declarative 
(conscious) memory for recent episodes and experi- 
ences. A disturbance in this function is known as an 
amnestic state. In the absence of deficits in motivation, 



attention, language, or visuospatial function, the clinical 
diagnosis of a persistent global amnestic state is always 
associated with bilateral damage to the limbic network, 
usually within the hippocampo-entorhinal complex or 
the thalamus. 

Although the limbic network is the site of damage 
for amnestic states, it is almost certainly not the storage 
site for memories. Memories are stored in widely dis- 
tributed form throughout the cerebral cortex. The role 
attributed to the limbic network is to bind these distrib- 
uted fragments into coherent events and experiences that 
can sustain conscious recall. Damage to the limbic net- 
work does not necessarily destroy memories but inter- 
feres with their conscious (declarative) recall in coherent 
form. The individual fragments of information remain 
preserved despite the limbic lesions and can sustain what 
is known as implicit memory- For example, patients with 
amnestic states can acquire new motor or perceptual 
skills, even though they may have no conscious knowl- 
edge of the experiences that led to the acquisition of these 
skills. 

The memory disturbance in the amnestic state is 
multimodal and includes retrograde and anterograde 
components. The retrograde amnesia involves an inability 
to recall experiences that occurred before the onset of 
the amnestic state. Relatively recent events are more 
vulnerable to retrograde amnesia than more remote and 
more extensively consolidated events. A patient who 
comes to the emergency department complaining that 
he cannot remember his identity but who can remem- 
ber the events of the previous day is almost certainly not 
suffering from a neurologic cause of memory distur- 
bance. The second and most important component of 
the amnestic state is the anterograde amnesia, which indi- 
cates an inability to store, retain, and recall new knowl- 
edge. Patients with amnestic states cannot remember 
what they ate a few minutes ago or the details of an 
important event they may have experienced a few hours 
ago. In the acute stages, there may also be a tendency to 
fill in memory gaps with inaccurate, fabricated, and 
often implausible information. This is known as confabu- 
lation. Patients with the amnestic syndrome forget that 
they forget and tend to deny the existence of a memory 
problem when questioned. 

The patient -with an amnestic state is almost always 
disoriented, especially to time. Accurate temporal orien- 
tation and accurate knowledge of current news rule out 
a major amnestic state. The anterograde component of 
an amnestic state can be tested with a list of four to five 
words read aloud by the examiner up to five times or 
until the patient can immediately repeat the entire list 
without intervening delay. In the next phase of testing, 
the patient is allowed to concentrate on the -words and 
to rehearse them internally for 1 min before being asked to 
recall them. Accurate performance in this phase indicates 
that the patient is motivated and sufficiently attentive to 



hold the words online for at least 1 min. The final phase 
of the testing involves a retention period of 5—10 min, 
during which the patient is engaged in other tasks. Ade- 
quate recall at the end of this interval requires offline 
storage, retention, and retrieval. Amnestic patients fail 
this phase of the task and may even forget that they 
were given a list of words to remember. Accurate recog- 
nition of the words by multiple choice in a patient who 
cannot recall them indicates a less severe memory dis- 
turbance that affects mostly the retrieval stage of memory. 
The retrograde component of an amnesia can be assessed 
with questions related to autobiographical or historic 
events. The anterograde component of amnestic states is 
usually much more prominent than the retrograde com- 
ponent. In rare instances, usually associated with tempo- 
ral lobe epilepsy or benzodiazepine intake, the retro- 
grade component may dominate. 

The assessment of memory can be quite challenging. 
Bedside evaluations may only detect the most severe 
impairments. Less severe memory impairments, as in the 
case of patients with temporal lobe epilepsy, mild head 
injury, or early dementia, require quantitative evaluations 
by neuropsychologists. Confusional states caused by toxic- 
metabolic encephalopathies and some types of frontal 
lobe damage interfere with attentional capacity and lead 
to secondary memory impairments, even in the absence 
of any limbic lesions. This sort of memory impairment 
can be differentiated from the amnestic state by the 
presence of additional impairments in the attention- 
related tasks described later in the section on the frontal 
lobes. 

Many neurologic diseases can give rise to an amnestic 
state. These include tumors (of the sphenoid wing, pos- 
terior corpus callosum, thalamus, or medial temporal 
lobe), infarctions (in the territories of the anterior or 
posterior cerebral arteries), head trauma, herpes simplex 
encephalitis, Wernicke -Korsakoff encephalopathy, para- 
neoplastic limbic encephalitis, and degenerative 
dementias such as Alzheimer's or Pick's disease. The one 
common denominator of all these diseases is that they 
lead to the bilateral lesions within one or more compo- 
nents in the limbic network, most commonly the hip- 
pocampus, entorhinal cortex, the mammillary bodies of 
the hypothalamus, and the limbic thalamus. Occasion- 
ally, unilateral left-sided lesions can give rise to an 
amnestic state, but the memory disorder tends to be 
transient. Depending on the nature and distribution of 
the underlying neurologic disease, the patient may also 
have visual field deficits, eye movement limitations, or 
cerebellar findings. 

Transient global amnesia is a distinctive syndrome usu- 
ally seen in late middle age. Patients become acutely dis- 
oriented and repeatedly ask who they are, where they 
are, what they are doing. The spell is characterized by 
anterograde amnesia (inability to retain new information) 
and a retrograde amnesia for relatively recent events that 



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occurred before the onset. The syndrome usually 
resolves within 24—48 h and is followed by the filling-in 
of the period affected by the retrograde amnesia, 
although there is persistent loss of memory for the events 
that occurred during the ictus. Recurrences are noted in 
~20% of patients. Migraine, temporal lobe seizures, and 
transient ischemic events in the posterior cerebral terri- 
tory have been postulated as causes of transient global 
amnesia. The absence of associated neurologic findings 
may occasionally lead to the incorrect diagnosis of a 
psychiatric disorder. 



THE PREFRONTAL NETWORK FOR 
ATTENTION AND BEHAVIOR 

Approximately one-third of all the cerebral cortex in 
the human brain is located in the frontal lobes. The 
frontal lobes can be subdivided into motor-premotor, 
dorsolateral prefrontal, medial prefrontal, and orbitofrontal 
components. The terms frontal lobe syndrome and prefrontal 
cortex refer only to the last three of these four compo- 
nents. These are the parts of the cerebral cortex that 
show the greatest phylogenetic expansion in primates and 
especially in humans. The dorsolateral prefrontal, medial 
prefrontal, and orbitofrontal areas, and the subcortical 
structures with which they are interconnected (i.e., the 
head of the caudate and the dorsomedial nucleus of the 
thalamus), collectively make up a large-scale network 
that coordinates exceedingly complex aspects of human 
cognition and behavior. 

The prefrontal network plays an important role in 
behaviors that require an integration of thought with 
emotion and motivation. There is no simple formula 
for summarizing the diverse functional affiliations of 
the prefrontal network. Its integrity appears important 
for the simultaneous awareness of context, options, 
consequences, relevance, and emotional impact so as 
to allow the formulation of adaptive inferences, deci- 
sions, and actions. Damage to this part of the brain 
impairs mental flexibility, reasoning, hypothesis forma- 
tion, abstract thinking, foresight, judgment, the online 
(attentive) holding of information, and the ability to 
inhibit inappropriate responses. Behaviors impaired by 
prefrontal cortex lesions, especially those related to the 
manipulation of mental content, are often referred to 
as "executive functions." 

Even very large bilateral prefrontal lesions may leave 
all sensory, motor, and basic cognitive functions intact 
while leading to isolated but dramatic alterations of per- 
sonality and behavior. The most common clinical mani- 
festations of damage to the prefrontal network take the 
form of two relatively distinct syndromes. In the frontal 
abulic syndrome, the patient shows a loss of initiative, cre- 
ativity, and curiosity and displays a pervasive emotional 
blandness and apathy. In the frontal disinhibition syndrome, 



the patient becomes socially disinhibited and shows 
severe impairments of judgment, insight, and foresight. 
The dissociation between intact cognitive function and 
a total lack of even rudimentary common sense is strik- 
ing. Despite the preservation of all essential memory 
functions, the patient cannot learn from experience and 
continues to display inappropriate behaviors without 
appearing to feel emotional pain, guilt, or regret when 
such behaviors repeatedly lead to disastrous consequences. 
The impairments may emerge only in real-life situations 
when behavior is under minimal external control and 
may not be apparent within the structured environment 
of the medical office. Testing judgment by asking 
patients what they would do if they detected a fire in a 
theater or found a stamped and addressed envelope on 
the road is not very informative since patients who answer 
these questions wisely in the office may still act very 
foolishly in the more complex real-life setting. The 
physician must therefore be prepared to make a diagno- 
sis of frontal lobe disease on the basis of historic infor- 
mation alone even when the office examination of mental 
state may be quite intact. 

The abulic syndrome tends to be associated with dam- 
age to the dorsolateral prefrontal cortex, and the disinhibi- 
tion syndrome with the medial prefrontal or orbitofrontal 
cortex. These syndromes tend to arise almost exclusively 
after bilateral lesions, most frequently in the setting of head 
trauma, stroke, ruptured aneurysms, hydrocephalus, tumors 
(including metastases, glioblastoma, and falx or olfactory 
groove meningiomas), or focal degenerative diseases. Uni- 
lateral lesions confined to the prefrontal cortex may remain 
silent until the pathology spreads to the other side. The 
emergence of developmentally primitive reflexes, also 
known as frontal release signs, such as grasping (elicited 
by stroking the palm) and sucking (elicited by stroking 
the lips) are seen primarily in patients with large struc- 
tural lesions that extend into the premotor components 
of the frontal lobes or in the context of metabolic 
encephalopathies. The vast majority of patients with pre- 
frontal lesions and frontal lobe behavioral syndromes do 
not display these reflexes. 

Damage to the frontal lobe disrupts a variety of 
attention-related functions including working memory 
(the transient online holding of information) , concentra- 
tion span, the scanning and retrieval of stored informa- 
tion, the inhibition of immediate but inappropriate 
responses, and mental flexibility. The capacity for focus- 
ing on a trend of thought and the ability to voluntarily 
shift the focus of attention from one thought or stimulus 
to another can become impaired. Digit span (which 
should be seven forward and five reverse) is decreased; 
the recitation of the months of the year in reverse order 
(which should take less than 1 5 s) is slowed; and the flu- 
ency in producing words starting with a,f, or s that can 
be generated in 1 min (normally ^12 per letter) is 
diminished even in nonaphasic patients. Characteristically, 



there is a progressive slowing of performance as the task 
proceeds; e.g., the patient asked to count backwards by 
3s may say "100, 97, 94, . . . 91, . . . 88," etc., and may not 
complete the task. In "go— no-go" tasks (where the instruc- 
tion is to raise the finger upon hearing one tap but to 
keep it still upon hearing two taps), the patient shows a 
characteristic inability to keep still in response to the 
"no-go" stimulus; mental flexibility (tested by the ability 
to shift from one criterion to another in sorting or match- 
ing tasks) is impoverished; distractibility by irrelevant stim- 
uli is increased; and there is a pronounced tendency for 
impersistence and perseveration. 

These attentional deficits disrupt the orderly registra- 
tion and retrieval of new information and lead to sec- 
ondary memory deficits. Such memory deficits can be 
differentiated from the primary memory impairments of 
the amnestic state by showing that they improve when 
the attentional load of the task is decreased. Working 
memory (also known as immediate memory) is an atten- 
tional function based on the temporary online holding of 
information. It is closely associated with the integrity of 
the prefrontal network and the ascending reticular activat- 
ing system. Retentive memory, on the other hand, depends 
on the stable (offline) storage of information and is associ- 
ated with the integrity of the limbic network. The dis- 
tinction of the underlying neural mechanisms is illustrated 
by the observation that severely amnestic patients who 
cannot remember events that occurred a few minutes ago 
may have intact if not superior working memory capacity 
as shown in tests of digit span. 

Lesions in the caudate nucleus or in the dorsomedial 
nucleus of the thalamus (subcortical components of the 
prefrontal network) can also produce a frontal lobe syn- 
drome. This is one reason why the mental state changes 
associated with degenerative basal ganglia diseases, such 
as Parkinson's or Huntington's disease, may take the 
form of a frontal lobe syndrome. Because of its wide- 
spread connections with other regions of association 
cortex, one essential computational role of the prefrontal 
network is to function as an integrator, or "orchestrator," 
for other networks. Bilateral multifocal lesions of the cere- 
bral hemispheres, none of which are individually large 
enough to cause specific cognitive deficits such as aphasia 
or neglect, can collectively interfere with the connectivity 
and integrating function of the prefrontal cortex. A 
frontal lobe syndrome is the single most common 
behavioral profile associated with a variety of bilateral mul- 
tifocal brain diseases including metabolic encephalopathy, 
multiple sclerosis, vitamin B 12 deficiency, and others. In 
fact, the vast majority of patients with the clinical diag- 
nosis of a frontal lobe syndrome tend to have lesions 
that do not involve prefrontal cortex but involve either 
the subcortical components of the prefrontal network or 
its connections with other parts of the brain. In order to 
avoid making a diagnosis of "frontal lobe syndrome" 
in a patient with no evidence of frontal cortex disease, 



it is advisable to use the diagnostic term frontal net- 153 
work syndrome, with the understanding that the respon- 
sible lesions can lie anywhere within this distributed 
network. 

The patient with frontal lobe disease raises potential 
dilemmas in differential diagnosis: the abulia and bland- 
ness may be misinterpreted as depression, and the disin- 
hibition as idiopathic mania or acting-out. Appropriate 
intervention may be delayed while a treatable tumor 
keeps expanding. An informed approach to frontal lobe 
disease and its behavioral manifestations may help to 
avoid such errors. 



CARING FOR THE PATIENT WITH 
DEFICITS OF HIGHER CEREBRAL 
FUNCTION 

Some of the deficits described in this chapter are so 
complex that they may bewilder not only the patient 
and family but also the physician. It is imperative to 
carry out a systematic clinical evaluation in order to 
characterize the nature of the deficits and explain them 
in lay terms to the patient and family. Such an explana- 
tion can allay at least some of the anxieties, address the 
mistaken impression that the deficit (e.g., social disinhi- 
bition or inability to recognize family members) is psy- 
chologically motivated, and lead to practical suggestions 
for daily living activities. The consultation of a skilled 
neuropsychologist may aid in the formulation of diag- 
nosis and management. Patients with simultanagnosia, for 
example, may benefit from the counterintuitive instruc- 
tion to stand back when they cannot find an item so 
that a greater search area falls within the immediate field 
of gaze. Some patients with frontal lobe disease can be 
extremely irritable and abusive to spouses and yet dis- 
play all the appropriate social graces during the visit to 
the medical office. In such cases, the history may be 
more important than the bedside examination in chart- 
ing a course of treatment. 

Reactive depression is common in patients with 
higher cerebral dysfunction and should be treated. These 
patients may be sensitive to the usual doses of antide- 
pressants or anxiolytics and deserve a careful titration of 
dosage. Brain damage may cause a dissociation between 
feeling states and their expression, so that a patient who 
may superficially appear jocular could still be suffering 
from an underlying depression that deserves to be treated. 
In many cases, agitation may be controlled with reassur- 
ance. In other cases, treatment with sedating antidepres- 
sants may become necessary. The use of neuroleptics for 
the control of agitation should be reserved for refractory 
cases since extrapyramidal side effects are frequent in 
patients with coexisting brain damage. 

Spontaneous improvement of cognitive deficits due 
to acute neurologic lesions is common. It is most rapid 



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in the first few weeks but may continue for up to 2 years, 
especially in young individuals with single brain lesions. 
The mechanisms for this recovery are incompletely 
understood. Some of the initial deficits appear to arise 
from remote dysfunction (diaschisis) in parts of the brain 
that are interconnected with the site of initial injury. 
Improvement in these patients may reflect, at least in 
part, a normalization of the remote dysfunction. Other 
mechanisms may involve functional reorganization in 
surviving neurons adjacent to the injury or the compen- 
satory use of homologous structures, e.g., the right supe- 
rior temporal gyrus with recovery from Wernicke's 
aphasia. In some patients with large lesions involving 
Broca's and Wernicke's areas, only Wernicke's area may 
show contralateral compensatory reorganization (or 
bilateral functionality), giving rise to a situation where a 
lesion that should have caused a global aphasia becomes 
associated with a residual Broca's aphasia. Prognosis for 
recovery from aphasia is best when Wernicke's area is 
spared. Cognitive rehabilitation procedures have been 
used in the treatment of higher cortical deficits. There 
are few controlled studies, but some do show a benefit 
of rehabilitation in the recovery from hemispatial 
neglect and aphasia. Some types of deficits may be more 
prone to recovery than others. For example, patients 
with nonfluent aphasias are more likely to benefit from 
speech therapy than patients with fluent aphasias and 
comprehension deficits. In general, lesions that lead to a 
denial of illness (e.g., anosognosia) are associated with 
cognitive deficits that are more resistant to rehabilita- 
tion. The recovery from higher cortical dysfunction is 
rarely complete. Periodic neuropsychological assessment 
is necessary for quantifying the pace of the improvement 
and for generating specific recommendations for cogni- 
tive rehabilitation, modifications in the home environ- 
ment, and the timetable for returning to school or work. 
In general medical practice, most patients with deficits 
in higher cognitive functions will be suffering from 
dementia. There is a mistaken belief that dementias are 
anatomically diffuse and that they cause global cognitive 
impairments. This is only true at the terminal stages. 
During most of the clinical course, dementias are exquisitely 
selective with respect to anatomy and cognitive pattern. 



Alzheimer's disease, for example, causes the greatest destruc- 
tion in medial temporal areas belonging to the memory 
network and is clinically characterized by a correspond- 
ingly severe amnesia. There are other dementias where 
memory is intact. Frontal lobe dementia results from a 
selective degeneration of the frontal lobe and leads to a 
gradual dissolution of behavior and complex attention. 
Primary progressive aphasia is characterized by a gradual 
atrophy of the left perisylvian language network and 
leads to a progressive dissolution of language that can 
remain isolated for up to 10 years. An enlightened 
approach to the differential diagnosis and treatment of 
these patients requires an understanding of the principles 
that link neural networks to higher cerebral functions. 

FURTHER READINGS 

CATANI M, FFYCHTE H: The rises and falls of disconnection syn- 
dromes. Brain 128:2224, 2005 

CRUTS M et al: Null mutations in progranulin cause ubiquitin- 
positive frontotemporal dementia linked to chromosome 17q21. 
Nature 442:916, 2006 

HlLLIS AE: Aphasia: Progress in the last quarter of a century. Neurol- 
ogy 69:200, 2007 

KNIBB JA et al: Clinical and pathological characterization of progres- 
sive aphasia. Ann Neurol 59:156, 2006 

Le Ber I et al: Phenotype variability in progranulin mutation carri- 
ers: a clinical, neuropsychological, imaging and genetic study. 
Brain 131:732,2008 

MESULAM M-M: Behavioral neuroanatomy: Large-scale networks, 
association cortex, frontal syndromes, the limbic system and 
hemispheric specializations, in Principles of Behavioral and Cogni- 
tive Neurology, 2d ed, M-M Mesulam (ed). New York, Oxford 
University Press, 2000, pp 1—120 

: Representation, inference, and transcendent encoding in 

neurocognitive networks of the human brain. Ann Neurol 
64:367,2008 

: Current concepts: Primary progressive aphasia — a language- 
based dementia. New Engl J Med 348:1535, 2003 

: The human frontal lobes: Transcending the default mode 



through contingent encoding, in Principles of Frontal Lobe Func- 
tion, DT Stuss, RT Knight (eds). New York, Oxford University 
Press, 2002, pp 8-30 

ROGALSKI E, MESULAM M: An update on primary progressive apha- 
sia. Curr Neurol Neurosci Rep 7:388, 2007 

SUMMERFIELD JJ et al: Orienting attention based on long-term 
memory experience. Neuron 49:905, 2006 




Charles A. Czeisler ■ John W. Winkelman ■ Gary S. Richardson 



Physiology of Sleep and Wakefulness 1 55 

States and Stages of Sleep 1 55 

Organization of Human Sleep 1 56 

Neuroanatomy of Sleep 1 56 

Neurochemistry of Sleep 1 57 

Physiology of Circadian Rhythmicity 1 57 

Behavioral Correlates of Sleep States and Stages 1 58 

Physiologic Correlates of Sleep States and Stages 1 58 

Disorders of Sleep and Wakefulness 1 59 

Evaluation of Insomnia 1 59 

Primary Insomnia 1 60 



Comorbid Insomnia 161 

Restless Legs Syndrome (RLS) 1 62 

Periodic Limb Movement Disorder (PLMD) 163 

Evaluation of Daytime Sleepiness 1 63 

Narcolepsy 164 

Sleep Apnea Syndromes 1 65 

Parasomnias 166 

Circadian Rhythm Sleep Disorders 1 67 

Medical Implications of Circadian Rhythmicity 169 

Further Readings 1 69 



Disturbed sleep is among the most frequent health com- 
plaints physicians encounter. More than one-half of 
adults in the United States experience at least intermit- 
tent sleep disturbances. For most, it is an occasional 
night of poor sleep or daytime sleepiness. However, the 
Institute of Medicine estimates that 50—70 million 
Americans suffer from a chronic disorder of sleep and 
wakefulness, which can lead to serious impairment of 
daytime functioning. In addition, such problems may 
contribute to or exacerbate medical or psychiatric con- 
ditions. Thirty years ago, many such complaints were 
treated with hypnotic medications without further diag- 
nostic evaluation. Since then, a distinct class of sleep and 
arousal disorders has been identified. 



PHYSIOLOGY OF SLEEP AND 
WAKEFULNESS 

Most adults sleep 7—8 h per night, although the timing, 
duration, and internal structure of sleep vary among 
healthy individuals and as a function of age. At the 
extremes, infants and the elderly have frequent interrup- 
tions of sleep. In the United States, adults of intermedi- 
ate age tend to have one consolidated sleep episode per 
day, although in some cultures sleep may be divided into 



a mid-afternoon nap and a shortened night sleep. Two 
principal systems govern the sleep-wake cycle: one 
actively generates sleep and sleep-related processes and 
another times sleep within the 24-h day. Either intrinsic 
abnormalities in these systems or extrinsic disturbances 
(environmental, drug- or illness-related) can lead to 
sleep or circadian rhythm disorders. 

STATES AND STAGES OF SLEEP 

States and stages of human sleep are defined on the basis 
of characteristic patterns in the electroencephalogram 
(EEG), the electrooculogram (EOG — a measure of eye- 
movement activity), and the surface electro myogram 
(EMG) measured on the chin and neck. The continuous 
recording of this array of electrophysiologic parameters to 
define sleep and wakefulness is termed polysomnography . 

Polysomnographic profiles define two states of sleep: 
(1) rapid-eye-movement (REM) sleep, and (2) non- 
rapid-eye-movement (NREM) sleep. NREM sleep is 
further subdivided into four stages, characterized by 
increasing arousal threshold and slowing of the cortical 
EEG. REM sleep is characterized by a low-amplitude, 
mixed-frequency EEG similar to that of NREM stage 1 
sleep. The EOG shows bursts of REM similar to those 
seen during eyes-open wakefulness. Chin EMG activity 



155 



156 is absent, reflecting the brainstem-mediated muscle atonia 
that is characteristic of that state. 



ORGANIZATION OF HUMAN SLEEP 

Normal nocturnal sleep in adults displays a consistent 
organization from night to night (Fig. 16-1). After sleep 
onset, sleep usually progresses through NREM stages 
1—4 within 45—60 min. Slow-wave sleep (NREM stages 
3 and 4) predominates in the first third of the night and 
comprises 15—25% of total nocturnal sleep time in 
young adults. The percentage of slow- wave sleep is 
influenced by several factors, most notably age (see 
below). Prior sleep deprivation increases the rapidity of 
sleep onset and both the intensity and amount of slow- 
wave sleep. 

The first REM sleep episode usually occurs in the 
second hour of sleep. More rapid onset of REM sleep in 
a young adult (particularly if <30 min) may suggest 
pathology such as endogenous depression, narcolepsy, 
circadian rhythm disorders, or drug withdrawal. NREM 
and REM alternate through the night with an average 
period of 90—110 min (the "ultradian" sleep cycle). 
Overall, REM sleep constitutes 20—25% of total sleep, 
and NREM stages 1 and 2 are 50-60%. 

Age has a profound impact on sleep state organization 
(Fig. 16-1). Slow-wave sleep is most intense and promi- 
nent during childhood, decreasing sharply at puberty and 
across the second and third decades of life. After age 30, 
there is a progressive decline in the amount of slow-wave 
sleep, and the amplitude of delta EEG activity comprising 
slow-wave sleep is profoundly reduced. The depth of 
slow-wave sleep, as measured by the arousal threshold to 
auditory stimulation, also decreases with age. In the other- 
wise healthy older person, slow-wave sleep may be com- 
pletely absent, particularly in males. 



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A different age profile exists for REM sleep than for 
slow-wave sleep. In infancy, REM sleep may comprise 
50% of total sleep time, and the percentage is inversely 
proportional to developmental age. The amount of 
REM sleep falls off sharply over the first postnatal year 
as a mature REM-NREM cycle develops; thereafter, 
REM sleep occupies a relatively constant percentage of 
total sleep time. 

NEUROANATOMY OF SLEEP 

Experimental studies in animals have variously impli- 
cated the medullary reticular formation, the thalamus, 
and the basal forebrain in the generation of sleep, while 
the brainstem reticular formation, the midbrain, the sub- 
thalamus, the thalamus, and the basal forebrain have all 
been suggested to play a role in the generation of wake- 
fulness or EEG arousal. 

Current models suggest that the capacity for sleep 
and wakefulness generation is distributed along an axial 
"core" of neurons extending from the brainstem ros- 
trally to the basal forebrain. A cluster of y-aminobutyric 
acid (GABA) and galaninergic neurons in the ventrolat- 
eral preoptic (VLPO) hypothalamus is selectively acti- 
vated coincident with sleep onset. These neurons project 
to and inhibit multiple distinct wakefulness centers 
including the tuberomammilary (histaminergic) nucleus 
that are important to the ascending arousal system, indi- 
cating that the hypothalamic VLPO neurons play a key 
executive role in sleep regulation. 

Specific regions in the pons are associated with the 
neurophysiologic correlates of REM sleep. Small lesions in 
the dorsal pons result in the loss of the descending muscle 
inhibition normally associated with RJ3M sleep; microin- 
jections of the cholinergic agonist carbachol into the pon- 
tine reticular formation appear to produce a state with all 



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Awake 




00:00 



FIGURE 16-1 

Stages of REM sleep (solid bars), the four stages of NREM 
sleep, and wakefulness over the course of the entire night for 
representative young and older adult men. Characteristic fea- 
tures of sleep in older people include reduction of slow-wave 



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04:00 
Clock time 



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06:00 



"i r 

08:00 



sleep, frequent spontaneous awakenings, early sleep onset, 
and early morning awakening. (From the Division of Sleep 
Medicine, Brigham and Women's Hospital.) 



of the features of REM sleep. These experimental manip- 
ulations are mimicked by pathologic conditions in humans 
and animals. In narcolepsy, for example, abrupt, complete, 
or partial paralysis (cataplexy) occurs in response to a vari- 
ety of stimuli. In dogs with this condition, physostigmine, a 
central cholinesterase inhibitor, increases the frequency of 
cataplectic attacks, while atropine decreases their fre- 
quency. Conversely, in REM sleep behavior disorder (see 
later), patients suffer from incomplete motor inhibition 
during REM sleep, resulting in involuntary, occasionally 
violent movement during REM sleep. 



NEUROCHEMISTRY OF SLEEP 

Early experimental studies that focused on the raphe 
nuclei of the brainstem appeared to implicate serotonin as 
the primary sleep-promoting neurotransmitter, while cat- 
echolamines were considered to be responsible for wake- 
fulness. Simple neurochemical models have given way to 
more complex formulations involving multiple parallel 
waking systems. Pharmacologic studies suggest that hista- 
mine, acetylcholine, dopamine, serotonin, and noradrena- 
line are all involved in wake promotion. In addition, pontine 
cholinergic neurotransmission is known to play a role in 
REM sleep generation. The alerting influence of caffeine 
implicates adenosine, whereas the hypnotic effect of ben- 
zodiazepines and barbiturates suggests a role for endogenous 
ligands of the GABA A receptor complex. A newly charac- 
terized neuropeptide, hypocretin (orexin), has recently been 
implicated in the pathophysiology of narcolepsy (see 
later), but its role in normal sleep regulation remains to be 
defined. 

A variety of sleep-promoting substances have been 
identified, although it is not known whether they are 
involved in the endogenous sleep-wake regulatory process. 
These include prostaglandin D 2 , delta sleep— inducing pep- 
tide, muramyl dipeptide, interleukin 1, fatty acid primary 
amides, and melatonin. The hypnotic effect of these sub- 
stances is commonly limited to NREM or slow-wave 
sleep, although peptides that increase REM sleep have also 
been reported. Many putative "sleep factors," including 
interleukin 1 and prostaglandin D 2 , are immunologically 
active as well, suggesting a link between immune function 
and sleep-wake states. 



PHYSIOLOGY OF CIRCADIAN RHYTHMICITY 

The sleep-wake cycle is the most evident of the many 
24-h rhythms in humans. Prominent daily variations also 
occur in endocrine, thermoregulatory, cardiac, pul- 
monary, renal, gastrointestinal, and neurobehavioral 
functions. At the molecular level, endogenous circadian 
rhythmicity is driven by self-sustaining transcriptional/ 
translational feedback loops (Fig. 16-2). In evaluating a 
daily variation in humans, it is important to distinguish 




157 



E-Box Perl gene 

FIGURE 16-2 

Model of the molecular feedback loop at the core of the 
mammalian circadian clock. The positive element of the 
feedback loop (+) is the transcriptional activation of the Perl 
gene (and probably other clock genes) by a heterodimer of 
the transcription factors CLOCK and BMAL1 (also called 
MOP3) bound to an E-box DNA regulatory element. The Perl 
transcript and its product, the clock component PER1 pro- 
tein, accumulate in the cell cytoplasm. As it accumulates, the 
PER1 protein is recruited into a multiprotein complex thought 
to contain other circadian clock component proteins such as 
cryptochromes (CRYs), Period proteins (PERs), and others. 
This complex is then transported into the cell nucleus (across 
the dotted line), where it functions as the negative element in 
the feedback loop (-) by inhibiting the activity of the CLOCK- 
BMAL1 transcription factor heterodimer. As a consequence 
of this action, the concentration of PER1 and other clock 
proteins in the inhibitory complex falls, allowing CLOCK- 
BMAL1 to activate transcription of Perl and other genes and 
begin another cycle. The dynamics of the 24-h molecular 
cycle are controlled at several levels, including regulation of 
the rate of PER protein degradation by casein kinase-1 
epsilon (CK1E). Additional limbs of this genetic regulatory 
network, omitted for the sake of clarity, are thought to con- 
tribute stability. Question marks denote putative clock pro- 
teins, such as Timeless (TIM), as yet lacking genetic proof of 
a role in the mammalian clock mechanism. (Copyright Charles 
J. Weitz, Ph.D., Department of Neurobiology, Harvard Med- 
ical School.) 



between those rhythmic components passively evoked 
by periodic environmental or behavioral changes (e.g., 
the increase in blood pressure and heart rate upon 
assumption of the upright posture) and those actively 
driven by an endogenous oscillatory process (e.g., the 
circadian variation in plasma Cortisol that persists under 
a variety of environmental and behavioral conditions) . 

While it is now recognized that many peripheral 
tissues in mammals have circadian clocks that regulate 
diverse physiologic processes, these independent tissue- 
specific oscillations are coordinated by a central neural 
pacemaker located in the suprachiasmatic nuclei (SCN) 
of the hypothalamus. Bilateral destruction of these nuclei 
results in a loss of the endogenous circadian rhythm of 









158 



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locomotor activity, which can be restored only by trans- 
plantation of the same structure from a donor animal. 
The genetically determined period of this endogenous 
neural oscillator, which averages ~24.2 h in humans, is 
normally synchronized to the 24-h period of the envi- 
ronmental light-dark cycle. Small differences in circadian 
period underlie variations in diurnal preference, with 
the circadian period shorter in individuals who typically 
rise early compared to those who typically go to bed late. 
Entrainment of mammalian circadian rhythms by the 
light-dark cycle is mediated via the retinohypothalamic 
tract, a monosynaptic pathway that links specialized, pho- 
toreceptive retinal ganglion cells directly to the SCN. 
Humans are exquisitely sensitive to the resetting effects 
of light, particularly at the blue end (~460— 480 nm) of 
the visible spectrum. 

The timing and internal architecture of sleep are 
directly coupled to the output of the endogenous circa- 
dian pacemaker. Paradoxically, the endogenous circadian 
rhythms of sleep tendency, sleepiness, and REM sleep 
propensity all peak near the habitual wake time, just 
after the nadir of the endogenous circadian temperature 
cycle, whereas the circadian wake propensity rhythm 
peaks 1—3 h before the habitual bedtime. These rhythms 
are thus timed to oppose the homeostatic decline of 
sleep tendency during the habitual sleep episode and the 
rise of sleep tendency throughout the usual waking day, 
respectively. Misalignment of the output of the endoge- 
nous circadian pacemaker with the desired sleep-wake 
cycle can, therefore, induce insomnia, decreased alert- 
ness, and impaired performance evident in night-shift 
workers and airline travelers. 

BEHAVIORAL CORRELATES OF SLEEP 
STATES AND STAGES 

Polysomnographic staging of sleep correlates with behav- 
ioral changes during specific states and stages. During the 
transitional state between wakefulness and sleep (stage 
1 sleep), subjects may respond to faint auditory or visual 
signals without "awakening." Memory incorporation is 
inhibited at the onset of NREM stage 1 sleep, which may 
explain why individuals aroused from that transitional sleep 
stage frequently deny having been asleep. Such transitions 
may intrude upon behavioral wakefulness after sleep depri- 
vation, notwithstanding attempts to remain continuously 
awake (see Shift-Work Disorder, later in the chapter) . 

Awakenings from PvEM sleep are associated with recall 
of vivid dream imagery >80% of the time. The reliability 
of dream recall increases with PvEM sleep episodes occur- 
ring later in the night. Imagery may also be reported after 
NREM sleep interruptions, though these typically lack 
the detail and vividness of REM sleep dreams. The inci- 
dence of NREM sleep dream recall can be increased by 
selective REM sleep deprivation, suggesting that REM 
sleep and dreaming per se are not inexorably linked. 



PHYSIOLOGIC CORRELATES OF SLEEP 
STATES AND STAGES 

All major physiologic systems are influenced by sleep. 
Changes in cardiovascular function include a decrease in 
blood pressure and heart rate during NREM and partic- 
ularly during slow-wave sleep. During REM sleep, pha- 
sic activity (bursts of eye movements) is associated with 
variability in both blood pressure and heart rate medi- 
ated principally by the vagus. Cardiac dysrhythmias may 
occur selectively during REM sleep. Respiratory func- 
tion also changes. In comparison to relaxed wakefulness, 
respiratory rate becomes more regular during NREM 
sleep (especially slow-wave sleep) and tonic REM sleep 
and becomes very irregular during phasic REM sleep. 
Minute ventilation decreases in NREM sleep out of 
proportion to the decrease in metabolic rate at sleep onset, 
resulting in a higher Pco 2 . 

Endocrine function also varies with sleep. Slow-wave 
sleep is associated -with secretion of growth hormone, 
while sleep in general is associated with augmented 
secretion of prolactin. Sleep has a complex effect on the 
secretion of luteinizing hormone (LH) : during puberty, 
sleep is associated with increased LH secretion, -whereas 
sleep in the postpuberal female inhibits LH secretion in 
the early follicular phase of the menstrual cycle. Sleep 
onset (and probably slow-wave sleep) is associated with 
inhibition of thyroid-stimulating hormone and of the 
adrenocorticotropic hormone— Cortisol axis, an effect that 
is superimposed on the prominent circadian rhythms in 
the two systems. 

The pineal hormone melatonin is secreted predomi- 
nantly at night in both day- and night-active species, 
reflecting the direct modulation of pineal activity by the 
circadian pacemaker through a circuitous neural pathway 
from the SCN to the pineal gland. Melatonin secretion 
is not dependent upon the occurrence of sleep, persist- 
ing in individuals kept awake at night. In addition, exoge- 
nous melatonin increases sleepiness and increases sleep 
duration when administered to healthy adults attempting 
to sleep during daylight hours, at a time when endoge- 
nous melatonin levels are low. The efficacy of melatonin 
as a sleep-promoting therapy for patients with insomnia 
is currently not known. 

Sleep is also accompanied by alterations of ther- 
moregulatory function. NPvEM sleep is associated with 
an attenuation of thermoregulatory responses to either 
heat or cold stress, and animal studies of thermosensitive 
neurons in the hypothalamus document an NREM- 
sleep-dependent reduction of the thermoregulatory set- 
point. REM sleep is associated with complete absence 
of thermoregulatory responsiveness, effectively resulting 
in functional poikilothermy However, the potential 
adverse impact of this failure of thermoregulation is 
blunted by inhibition of REM sleep by extreme ambient 
temperatures. 



DISORDERS OF SLEEP AND 
WAKEFULNESS 



Approach to the Patient: 

SLEEP DISORDERS 

Patients may seek help from a physician because of 
one of several symptoms: (1) an acute or chronic 
inability to initiate or maintain sleep adequately at 
night (insomnia); (2) chronic fatigue, sleepiness, or 
tiredness during the day; or (3) a behavioral manifes- 
tation associated with sleep itself. Complaints of 
insomnia or excessive daytime sleepiness should be 
approached as symptoms (much like fever or pain) of 
underlying disorders. Knowledge of the differential 
diagnosis of these presenting complaints is essential to 
identify any underlying medical disorder. Only then 
can appropriate treatment, rather than nonspecific 
approaches (e.g., over-the-counter sleeping aids), be 
applied. Diagnoses of exclusion, such as primary 
insomnia, should be made only after other diagnoses 
have been ruled out. Table 16-1 outlines the diag- 
nostic and therapeutic approach to the patient with a 
complaint of excessive daytime sleepiness. 

A careful history is essential. In particular, the dura- 
tion, severity, and consistency of the symptoms are 
important, along with the patient's estimate of the 
consequences of the sleep disorder on waking func- 
tion. Information from a friend or family member 



can be invaluable; some patients may be unaware of, 
or will underreport, such potentially embarrassing 
symptoms as heavy snoring or falling asleep while 
driving. 

Patients with excessive sleepiness should be advised 
to avoid all driving until effective therapy has been 
achieved. 

Completion by the patient of a day-by-day sleep- 
work-drug log for at least 2 weeks can help the physi- 
cian understand the nature of the complaint better. 
Work times and sleep times (including daytime naps 
and nocturnal awakenings) as well as drug and alco- 
hol use, including caffeine and hypnotics, should be 
noted each day. 

Polysomnography is necessary for the diagnosis of 
specific disorders such as narcolepsy and sleep apnea 
and may be of utility in other settings as well. In 
addition to the three electrophysiologic variables used 
to define sleep states and stages, the standard clinical 
polysomnogram includes measures of respiration (res- 
piratory effort, air flow, and oxygen saturation), ante- 
rior tibialis EMG, and electrocardiogram. 



EVALUATION OF INSOMNIA 

Insomnia is the complaint of inadequate sleep; it can be 
classified according to the nature of sleep disruption and 
the duration of the complaint. Insomnia is subdivided 
into difficulty falling asleep (sleep onset insomnia), frequent 
or sustained awakenings (sleep maintenance insomnia), early 



159 



CO 
CO 






TABLE 16-1 



EVALUATION OF THE PATIENT WITH THE COMPLAINT OF EXCESSIVE DAYTIME SOMNOLENCE 



FINDINGS ON HISTORY AND 
PHYSICAL EXAMINATION 



DIAGNOSTIC EVALUATION DIAGNOSIS 



THERAPY 



Obesity, snoring, hypertension 


Polysomnography with 


Obstructive 


Continuous positive airway pressure; 




respiratory monitoring 


sleep apnea 


ENT surgery (e.g., uvulopalatopharyngoplasty); 
dental appliance; pharmacologic therapy (e.g., 
protriptyline); weight loss 


Cataplexy, hypnogogic 


Polysomnography with 


Narcolepsy- 


Stimulants (e.g., modafinil, methylphenidate); 


hallucinations, sleep 


multiple sleep latency 


cataplexy 


REM-suppressant antidepressants (e.g., 


paralysis, family history 


testing 


syndrome 


protriptyline); genetic counseling 


Restless legs, disturbed 


Assesment for 


Restless legs 


Treatment of predisposing condition, if possible; 


sleep, predisposing 


predisposing medical 


syndrome 


dopamine agonists (e.g., pramipexole, 


medical condition (e.g., iron 


conditions 




ropinirole) 


deficiency or renal failure) 








Disturbed sleep, predisposing 


Sleep-wake diary 


Insomnias 


Treatment of predisposing condition and/or 


medical conditions (e.g., 


recording 


(see text) 


change in therapy, if possible; behavioral 


asthma) and/or predisposing 






therapy; short-acting benzodiazepine receptor 


medical therapies (e.g., 






agonist (e.g., Zolpidem) 


theophylline) 









Note: ENT, ears, nose, throat; REM, rapid eye movement; EMG, electromyogram. 



160 



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morning awakenings (sleep offset insomnia), or persistent 
sleepiness/fatigue despite sleep of adequate duration 
(nonrestorative sleep). Similarly, the duration of the symp- 
tom influences diagnostic and therapeutic considera- 
tions. An insomnia complaint lasting one to several 
nights (within a single episode) is termed transient insom- 
nia and is typically the result of situational stress or a 
change in sleep schedule or environment (e.g., jet lag 
disorder). Short-term insomnia lasts from a few days to 
3 weeks. Disruption of this duration is usually associated 
with more protracted stress, such as recovery from 
surgery or short-term illness. Long-term insomnia, or 
chronic insomnia, lasts for months or years and, in contrast 
with short-term insomnia, requires a thorough evalua- 
tion of underlying causes (see below) . Chronic insomnia 
is often a waxing and waning disorder, with spontaneous 
or stressor-induced exacerbations. 

An occasional night of poor sleep, typically in the set- 
ting of stress or excitement about external events, is both 
common and without lasting consequences. However, 
persistent insomnia can lead to impaired daytime func- 
tion, injury due to accidents, and the development of 
major depression. In addition, there is emerging evidence 
that individuals with chronic insomnia have increased uti- 
lization of health care resources, even after controlling for 
co-morbid medical and psychiatric disorders. 

All insomnias can be exacerbated and perpetuated by 
behaviors that are not conducive to initiating or main- 
taining sleep. Inadequate sleep hygiene is characterized by a 
behavior pattern prior to sleep or a bedroom environ- 
ment that is not conducive to sleep. Noise or light in the 
bedroom can interfere with sleep, as can a bed partner 
with periodic limb movements during sleep or one who 
snores loudly. Clocks can heighten the anxiety about the 
time it has taken to fall asleep. Drugs that act on the 
central nervous system, large meals, vigorous exercise, or 
hot showers just before sleep may all interfere with sleep 
onset. Many individuals participate in stressful work- 
related activities in the evening, producing a state 
incompatible with sleep onset. In preference to hypnotic 
medications, patients should be counseled to avoid 
stressful activities before bed, develop a soporific bed- 
time ritual, and to prepare and reserve the bedroom 
environment for sleeping. Consistent, regular rising 
times should be maintained daily, including weekends. 

PRIMARY INSOMNIA 

Many patients with chronic insomnia have no clear, 
single identifiable underlying cause for their difficulties 
with sleep. Rather, such patients often have multiple eti- 
ologies for their insomnia, which may evolve over the 
years. In addition, the chief sleep complaint may change 
over time, with initial insomnia predominating at one 
point, and multiple awakenings or nonrestorative sleep 



occurring at other times. Subsyndromal psychiatric 
disorders (e.g., anxiety and mood complaints), negative 
conditioning to the sleep environment (psychophysio- 
logic insomnia, see later in the chapter), amplification of 
the time spent awake (paradoxical insomnia), physiologic 
hyperarousal, and poor sleep hygiene (see earlier) may all 
be present. As these processes may be both causes and 
consequences of chronic insomnia, many individuals 
will have a progressive course to their symptoms in 
which the severity is proportional to the chronicity, and 
much of the complaint may persist even after effective 
treatment of the initial inciting etiology. Treatment of 
insomnia is often directed to each of the putative con- 
tributing factors: behavior therapies for anxiety and neg- 
ative conditioning (see later), pharmacotherapy and/or 
psychotherapy for mood/anxiety disorders, and an 
emphasis on maintenance of good sleep hygiene. 

If insomnia persists after treatment of these contribut- 
ing factors, empirical pharmacotherapy is often used on 
a nightly or intermittent basis. A variety of sedative 
compounds are used for this purpose. Alcohol and anti- 
histamines are the most commonly used nonprescrip- 
tion sleep aids. The former may help with sleep onset 
but is associated with sleep disruption during the night 
and can escalate into abuse, dependence, and withdrawal 
in the predisposed individual. Antihistamines may be of 
benefit when used intermittently but often produce 
rapid tolerance and may have multiple side effects (espe- 
cially anticholinergic), which limit their use, particularly 
in the elderly. Benzodiazepine-receptor agonists are the 
most effective and well-tolerated class of medications for 
insomnia. The broad range of half-lives allows flexibility 
in the duration of sedative action. The most commonly 
prescribed agents in this family are zaleplon (5—20 mg), 
with a half-life of 1—2 h; Zolpidem (5—10 mg) and tria- 
zolam (0.125—0.25 mg), with half-lives of 2— 3 h; eszopi- 
clone (1—3 mg), with a half-life of 5.5—8 h; and 
temazepam (15—30 mg) and lorazepam (0.5—2 mg),with 
half-lives of 6—12 h. Generally, side effects are minimal 
when the dose is kept low and the serum concentration 
is minimized during the waking hours (by using the 
shortest-acting, effective agent). Recent data suggest that 
at least one benzodiazepine receptor agonist (eszopi- 
clone) continues to be effective for 6 months of nightly 
use. However, longer durations of use have not been 
evaluated, and it is unclear whether this is true of other 
agents in this class. Moreover, with even brief continu- 
ous use of benzodiazepine-receptor agonists, rebound 
insomnia can occur upon discontinuation. The likeli- 
hood of rebound insomnia and tolerance can be mini- 
mized by short durations of treatment, intermittent use, 
or gradual tapering of the dose. For acute insomnia, 
nighdy use of a benzodiazepine receptor agonist for a max- 
imum of 2—4 weeks is advisable. For chronic insomnia, 
intermittent use is recommended, unless the consequences 



of untreated insomnia outweigh concerns regarding 
chronic use. Benzodiazepine receptor agonists should be 
avoided, or used very judiciously, in patients with a his- 
tory of substance or alcohol abuse. The heterocyclic 
antidepressants (trazodone, amitriptyline, and doxepin) 
are the most commonly prescribed alternatives to ben- 
zodiazepine receptor agonists due to their lack of abuse 
potential and lower cost. Trazodone (25-100 mg) is used 
more commonly than the tricyclic antidepressants as it 
has a much shorter half-life (5-9 h), has much less anti- 
cholinergic activity (sparing patients, particularly the 
elderly, constipation, urinary retention, and tachycardia), 
is associated with less weight gain, and is much safer in 
overdose. The risk of priapism is small (~1 in 10,000). 

Psychophysiologic Insomnia 

Persistent psychophysiologic insomnia is a behavioral disorder 
in which patients are preoccupied with a perceived inabil- 
ity to sleep adequately at night. This sleep disorder begins 
like any other acute insomnia; however, the poor sleep 
habits and sleep-related anxiety ("insomnia phobia") per- 
sist long after the initial incident. Such patients become 
hyperaroused by their own efforts to sleep or by the sleep 
environment, and the insomnia becomes a conditioned or 
learned response. Patients may be able to fall asleep more 
easily at unscheduled times (when not trying) or outside 
the home environment. Polysomnographic recording in 
patients with psychophysiologic insomnia reveals an 
objective sleep disturbance, often with an abnormally long 
sleep latency; frequent nocturnal awakenings; and an 
increased amount of stage 1 transitional sleep. Rigorous 
attention should be paid to improving sleep hygiene, cor- 
rection of counterproductive, arousing behaviors before 
bedtime, and minimizing exaggerated beliefs regarding the 
negative consequences of insomnia. Behavioral therapies 
are the treatment modality of choice, with intermittent use 
of medications. When patients are awake for >20 min, 
they should read or perform other relaxing activities to 
distract themselves from insomnia-related anxiety. In addi- 
tion, bedtime and wake time should be scheduled to 
restrict time in bed to be equal to their perceived total 
sleep time. This will generally produce sleep deprivation, 
greater sleep drive, and, eventually, better sleep. Time in 
bed can then be gradually expanded. In addition, methods 
directed toward producing relaxation in the sleep setting 
(e.g., meditation, muscle relaxation) are encouraged. 

Adjustment Insomnia (Acute Insomnia) 

This typically develops after a change in the sleeping 
environment (e.g., in an unfamiliar hotel or hospital 
bed) or before or after a significant life event, such as a 
change of occupation, loss of a loved one, illness, or anx- 
iety over a deadline or examination. Increased sleep 



latency, frequent awakenings from sleep, and early morn- 
ing awakening can all occur. Recovery is generally 
rapid, usually within a few weeks. Treatment is sympto- 
matic, with intermittent use of hypnotics and resolution 
of the underlying stress. Altitude insomnia describes a 
sleep disturbance that is a common consequence of 
exposure to high altitude. Periodic breathing of the 
Cheyne-Stokes type occurs during NREM sleep about 
half the time at high altitude, with restoration of a regu- 
lar breathing pattern during REM sleep. Both hypoxia 
and hypocapnia are thought to be involved in the devel- 
opment of periodic breathing. Frequent awakenings and 
poor quality sleep characterize altitude insomnia, which is 
generally worse on the first few nights at high altitude but 
may persist. Treatment with acetazolamide can decrease 
time spent in periodic breathing and substantially reduce 
hypoxia during sleep. 



COMORBID INSOMNIA 

Insomnia Associated with Mental Disorders 

Approximately 80% of patients with psychiatric disorders 
describe sleep complaints. There is considerable hetero- 
geneity, however, in the nature of the sleep disturbance 
both between conditions and among patients with the 
same condition. Depression can be associated with sleep 
onset insomnia, sleep maintenance insomnia, or early 
morning wakefulness. However, hypersomnia occurs in 
some depressed patients, especially adolescents and those 
with either bipolar or seasonal (fall/winter) depression 
(Chap. 49). Indeed, sleep disturbance is an important 
vegetative sign of depression and may commence before 
any mood changes are perceived by the patient. Consis- 
tent polysomnographic findings in depression include 
decreased REM sleep latency, lengthened first REM 
sleep episode, and shortened first NREM sleep episode; 
however, these findings are not specific for depression, 
and the extent of these changes varies with age and 
symptomatology. Depressed patients also show decreased 
slow-wave sleep and reduced sleep continuity. 

In mania and hypomania, sleep latency is increased and 
total sleep time can be reduced. Patients with anxiety disor- 
ders tend not to show the changes in PJ3M sleep and slow- 
wave sleep seen in endogenously depressed patients. Chronic 
alcoholics lack slow-wave sleep, have decreased amounts of 
PJiM sleep (as an acute response to alcohol), and have fre- 
quent arousals throughout the night. This is associated with 
impaired daytime alertness. The sleep of chronic alcoholics 
may remain disturbed for years after discontinuance of 
alcohol usage. Sleep architecture and physiology are dis- 
turbed in schizophrenia (with a decreased amount of stage 4 
sleep and a lack of augmentation of REM sleep following 
PJiM sleep deprivation); chronic schizophrenics often 
show day-night reversal, sleep fragmentation, and insomnia. 



161 






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162 Insomnia Associated with Neurologic 
Disorders 



A variety of neurologic diseases result in sleep disruption 
through both indirect, nonspecific mechanisms (e.g., pain 
in cervical spondylosis or low back pain) or by impair- 
ment of central neural structures involved in the genera- 
tion and control of sleep itself. For example, dementia 
from any cause has long been associated with distur- 
bances in the timing of the sleep- wake cycle, often char- 
acterized by nocturnal wandering and an exacerbation of 
symptomatology at night (so-called sundowning). 

Epilepsy may rarely present as a sleep complaint 
(Chap. 20). Often the history is of abnormal behavior, at 
times with convulsive movements during sleep. The dif- 
ferential diagnosis includes REM sleep behavior disor- 
der, sleep apnea syndrome, and periodic movements of 
sleep (see earlier) . Diagnosis requires nocturnal polysomno- 
graphy with a full EEG montage. Other neurologic dis- 
eases associated with abnormal movements, such as 
Parkinson's disease, hemiballismus, Huntington's chorea, and 
Tourette syndrome (Chaps. 24 and 25), are also associated 
with disrupted sleep, presumably through secondary mech- 
anisms. However, the abnormal movements themselves are 
greatly reduced during sleep. Headache syndromes (migraine 
or cluster headache) may show sleep-associated exacerba- 
tions (Chap. 6) by unknown mechanisms. 

Fatal familial insomnia is a rare hereditary disorder caused 
by degeneration of anterior and dorsomedial nuclei of the 
thalamus. Insomnia is a prominent early symptom. Patients 
develop progressive autonomic dysfunction, followed by 
dysarthria, myoclonus, coma, and death. The pathogenesis 
is a mutation in the prion gene (Chap. 38). 



ST 
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Insomnia Associated with Other 
Medical Disorders 

A number of medical conditions are associated with dis- 
ruptions of sleep. The association is frequently nonspe- 
cific, e.g., sleep disruption due to chronic pain from 
rheumatologic disorders. Attention to this association is 
important in that sleep-associated symptoms are often 
the presenting or most bothersome complaint. Treatment 
of the underlying medical problem is the most useful 
approach. Sleep disruption can also result from the use of 
medications such as glucocorticoids (see later). 

One prominent association is between sleep disrup- 
tion and asthma. In many asthmatics there is a prominent 
daily variation in airway resistance that results in marked 
increases in asthmatic symptoms at night, especially during 
sleep. In addition, treatment of asthma with theophylline- 
based compounds, adrenergic agonists, or glucocorticoids 
can independently disrupt sleep. When sleep disruption 
is a side effect of asthma treatment, inhaled glucocorti- 
coids (e.g., beclomethasone) that do not disrupt sleep 
may provide a useful alternative. 



Cardiac ischemia may also be associated with sleep dis- 
ruption. The ischemia itself may result from increases in 
sympathetic tone as a result of sleep apnea. Patients may 
present with complaints of nightmares or vivid, disturbing 
dreams, with or without awareness of the more classic 
symptoms of angina or of the sleep disordered breathing. 
Treatment of the sleep apnea may substantially improve 
the angina and the nocturnal sleep quality. Paroxysmal 
nocturnal dyspnea can also occur as a consequence of sleep- 
associated cardiac ischemia that causes pulmonary conges- 
tion exacerbated by the recumbent posture. 

Chronic obstructive pulmonary disease is also associated 
with sleep disruption, as is cystic fibrosis, menopause, hyper- 
thyroidism, gastroesophageal reflux, chronic renal failure, and 
liver failure. 

Medication-, Drug-, or Alcohol-Dependent 
Insomnia 

Disturbed sleep can result from ingestion of a wide vari- 
ety of agents. Caffeine is perhaps the most common phar- 
macologic cause of insomnia. It produces increased 
latency to sleep onset, more frequent arousals during 
sleep, and a reduction in total sleep time for up to 8—14 h 
after ingestion. Even small amounts of coffee can signifi- 
cantly disturb sleep in some patients; therefore, a 1- to 
2-month trial without caffeine should be attempted in 
patients with these symptoms. Similarly, alcohol and nico- 
tine can interfere with sleep, despite the fact that many 
patients use them to relax and promote sleep. Although 
alcohol can increase drowsiness and shorten sleep latency, 
even moderate amounts of alcohol increase awakenings in 
the second half of the night. In addition, alcohol ingestion 
prior to sleep is contraindicated in patients with sleep 
apnea because of the inhibitory effects of alcohol on 
upper airway muscle tone. Acutely, amphetamines and 
cocaine suppress both PJEM sleep and total sleep time, 
which return to normal with chronic use. Withdrawal 
leads to a REM sleep rebound. A number of prescribed 
medications can produce insomnia. Antidepressants, sym- 
pathomimetics, and glucocorticoids are common causes. 
In addition, severe rebound insomnia can result from the 
acute withdrawal of hypnotics, especially following the 
use of high doses of benzodiazepines with a short half- 
life. For this reason, hypnotic doses should be low to 
moderate and prolonged drug tapering is encouraged. 

RESTLESS LEGS SYNDROME (RLS) 

Patients with this sensory-motor disorder report an irre- 
sistible urge to move the legs, or sometimes the upper 
extremities that is often associated with a creepy-crawling 
or aching dysesthesias deep within the affected limbs. For 
most patients with RLS, the dysesthesias and restlessness 
are much worse in the evening or night compared to the 
daytime and frequently interferes with the ability to fall 



asleep. The symptoms appear with inactivity and are tem- 
porarily relieved by movement. In contrast, paresthesias 
secondary to peripheral neuropathy persist with activity. 
The severity of this chronic disorder may wax and wane 
over time and can be exacerbated by sleep deprivation, 
caffeine, alcohol, serotonergic antidepressants, and preg- 
nancy. The prevalence is 1—5% of young to middle-aged 
adults and 10-20% of those >60 years. There appear to be 
important differences in RLS prevalence among racial 
groups, with higher prevalence in those of Northern 
European ancestry. Roughly one-third of patients (partic- 
ularly those with an early age of onset) will have multiple 
affected family members. At least three separate chromoso- 
mal loci have been identified in familial RLS, though no 
gene has been identified to date. Iron deficiency and renal 
failure may cause RLS, which is then considered sec- 
ondary RLS. The symptoms of RLS are exquisitely sensi- 
tive to dopaminergic drugs (e.g., pramipexole 0.25—0.5 
mg q8PM or ropinirole 0.5—4.0 mg q8PM), which are the 
treatments of choice. Opiods, benzodiazepines, and 
gabapentin may also be of therapeutic value. Most patients 
with restless legs also experience periodic limb movements 
of sleep, although the reverse is not the case. 

PERIODIC LIMB MOVEMENT DISORDER 
(PLMD) 

Periodic limb movements of sleep (PLMS), previously known 
as nocturnal myoclonus, consists of stereotyped, 0.5- to 



5.0-s extensions of the great toe and dorsiflexion of the 163 
foot, which recur every 20—40 s during NREM sleep, in 
episodes lasting from minutes to hours, as documented 
by bilateral surface EMG recordings of the anterior tib- 
ialis on polysomnography. PLMS is the principal objec- 
tive polysomnographic finding in 17% of patients with 
insomnia and 11% of those with excessive daytime som- 
nolence (Fig. 16-3). It is often unclear whether it is an 
incidental finding or the cause of disturbed sleep. When 
deemed to be the latter, PLMS is called PLMD. PLMS 
occurs in a wide variety of sleep disorders (including 
narcolepsy, sleep apnea, REM sleep behavior disorder, 
and various forms of insomnia) and may be associated 
with frequent arousals and an increased number of 
sleep-stage transitions. The pathophysiology is not well 
understood, though individuals with high spinal transec- 
tions can exhibit periodic leg movements during sleep, 
suggesting the existence of a spinal generator. Treatment 
options include dopaminergic medications or benzodi- 
azepines. 



EVALUATION OF DAYTIME SLEEPINESS 

Daytime impairment due to sleep loss may be difficult 
to quantify for several reasons. First, sleepiness is not 
necessarily proportional to subjectively assessed sleep 
deprivation. In obstructive sleep apnea, for example, the 
repeated brief interruptions of sleep associated with 
resumption of respiration at the end of apneic episodes 






Snoring sounds I »| [ — h k « 



! ■»► 1 



mr ^ HWHM E * > 



Nasal/oral airflow 



Respiratory effort 



« AM/U Wat- f Wj\ / 



Arterial 2 saturation 94 93 



98 97 ac 

95 a/ 96 95 



90 89 



93 g1 92 



95 g 4 



97 98 98 98 



92 90 92 



90 88 90 
86 

-30 s 1 



EEG 



Chin EMG 



Heart Rate 



R.A.T. EMG 



L.A.T. EMG 



B 



\ ' I " 



+,.*,*.+, „ - , 



«-*■ 



+ 



1 — h — 1 — 1 — 1 — h 



+ 



^ — h 



^ — i- 



FIGURE 16-3 

Polysomnographic recordings of (A) obstructive sleep 
apnea and (S) periodic limb movement of sleep. Note the 
snoring and reduction in air flow in the presence of continued 
respiratory effort, associated with the subsequent oxygen 
desaturation (upper panel). Periodic limb movements occur 



-30s- 



with a relatively constant intermovement interval and are 
associated with changes in the EEG and heart rate accelera- 
tion (lower panel). R.A.T, right anterior tibialis; L.A.T., left 
anterior tibialis. (From the Division of Sleep Medicine, 
Brigham and Women's Hospital.) 



164 



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result in daytime sleepiness, despite the fact that the 
patient may be unaware of the sleep fragmentation. 
Second, subjective descriptions of waking impairment 
vary from patient to patient. Patients may describe them- 
selves as "sleepy," "fatigued," or "tired" and may have a 
clear sense of the meaning of those terms, while others 
may use the same terms to describe a completely differ- 
ent condition. Third, sleepiness, particularly when pro- 
found, may affect judgment in a manner analogous to 
ethanol, such that subjective awareness of the condition 
and the consequent cognitive and motor impairment is 
reduced. Finally, patients may be reluctant to admit that 
sleepiness is a problem, both because they are generally 
unaware of what constitutes normal alertness and 
because sleepiness is generally viewed pejoratively, 
ascribed more often to a deficit in motivation than to an 
inadequately addressed physiologic sleep need. 

Specific questioning about the occurrence of sleep 
episodes during normal waking hours, both intentional 
and unintentional, is necessary to determine the extent 
of the adverse effects of sleepiness on a patient's daytime 
function. Specific areas to be addressed include the 
occurrence of inadvertent sleep episodes while driving 
or in other safety-related settings, sleepiness while at 
work or school (and the relationship of sleepiness to 
work and school performance), and the effect of sleepi- 
ness on social and family life. Driving is particularly haz- 
ardous for patients with increased sleepiness. Reaction 
time is equally impaired by 24 h of sleep loss as by a 
blood alcohol level of 0.10 g/dL. More than half of 
Americans admit to driving when drowsy. An estimated 
250,000 motor vehicle crashes per year are due to 
drowsy drivers, thus causing 20% of all serious crash 
injuries. Drowsy driving legislation, aimed at improving 
education of all drivers about the hazards of driving 
drowsy and establishing sanctions comparable to those 
for drunk driving, is pending in several states. Screening 
for sleep disorders, provision of an adequate number of 
safe highway rest areas, maintenance of unobstructed 
shoulder rumble strips, and strict enforcement and com- 
pliance monitoring of hours-of-service policies are 
needed to reduce the risk of sleep-related transportation 
crashes. Evidence for significant daytime impairment [in 
association either with the diagnosis of a primary sleep 
disorder, such as narcolepsy or sleep apnea, or with 
imposed or self-selected sleep-wake schedules (see Shift- 
Work Disorder, later)] raises the issue of the physician's 
responsibility to notify motor vehicle licensing authori- 
ties of the increased risk of sleepiness-related vehicle 
accidents. As with epilepsy, legal requirements vary from 
state to state, and existing legal precedents do not pro- 
vide a consistent interpretation of the balance between 
the physician's responsibility and the patient's right to 
privacy. At a minimum, physicians should document dis- 
cussions with the patient regarding the increased risk of 
operating a vehicle, as well as a recommendation that 



driving be suspended until successful treatment or a 
schedule modification can be instituted. 

The distinction between fatigue and sleepiness can be 
useful in the differentiation of patients with complaints 
of fatigue or tiredness in the setting of disorders such as 
fibromyalgia, chronic fatigue syndrome (Chap. 47), or 
endocrine deficiencies such as hypothyroidism or Addi- 
son's disease. Although patients with these disorders can 
typically distinguish their daytime symptoms from the 
sleepiness that occurs with sleep deprivation, substantial 
overlap can occur. This is particularly true when the pri- 
mary disorder also results in chronic sleep disruption 
(e.g., sleep apnea in hypothyroidism) or in abnormal 
sleep (e.g., fibromyalgia). 

Although clinical evaluation of the complaint of 
excessive sleepiness is usually adequate, objective quan- 
tification is sometimes necessary. Assessment of daytime 
functioning as an index of the adequacy of sleep can be 
made with the multiple sleep latency test (MSLT), which 
involves repeated measurement of sleep latency (time to 
onset of sleep) under standardized conditions during a 
day following quantified nocturnal sleep. The average 
latency across four to six tests (administered every 2 h 
across the waking day) provides an objective measure of 
daytime sleep tendency. Disorders of sleep that result in 
pathologic daytime somnolence can be reliably distin- 
guished with the MSLT. In addition, the multiple mea- 
surements of sleep onset may identify direct transitions 
from wakefulness to REM sleep that are suggestive of 
specific pathologic conditions (e.g., narcolepsy). 

NARCOLEPSY 

Narcolepsy is both a disorder of the ability to sustain 
wakefulness voluntarily and a disorder of REM sleep 
regulation (Table 16-2). The classic "narcolepsy tetrad" 
consists of excessive daytime somnolence plus three spe- 
cific symptoms related to an intrusion of REM sleep 
characteristics (e.g., muscle atonia, vivid dream imagery) 
into the transition between wakefulness and sleep: 



TABLE 16-2 



PREVALENCE OF SYMPTOMS IN NARCOLEPSY 



SYMPTOM 


PREVALENCE, % 


Excessive daytime somnolence 


100 


Disturbed sleep 


87 


Cataplexy 


76 


Hypnagogic hallucinations 


68 


Sleep paralysis 


64 


Memory problems 


50 



Source: Modified from TA Roth, L Merlotti in SA Burton et al (eds), 
Narcolepsy 3rd International Symposium: Selected Symposium Pro- 
ceedings, Chicago, Matrix Communications, 1989. 



(1) sudden weakness or loss of muscle tone without loss 
of consciousness, often elicited by emotion (cataplexy); 

(2) hallucinations at sleep onset (hypnogogic hallucina- 
tions) or upon awakening (hypnopompic hallucinations); 
and (3) muscle paralysis upon awakening (sleep paralysis) . 
The severity of cataplexy varies, as patients may have two 
to three attacks per day or per decade. Some patients 
with objectively confirmed narcolepsy (see later) may 
show no evidence of cataplexy. In those with cataplexy, 
the extent and duration of an attack may also vary, from 
a transient sagging of the jaw lasting a few seconds to 
rare cases of flaccid paralysis of the entire voluntary 
musculature for up to 20—30 min. Symptoms of nar- 
colepsy typically begin in the second decade, although 
the onset ranges from ages 5—50. Once established, the 
disease is chronic without remissions. Secondary forms 
of narcolepsy have been described (e.g., after head 
trauma) . 

Narcolepsy affects about 1 in 4000 people in the 
United States and appears to have a genetic basis. 
Recently, several convergent lines of evidence suggest 
that the hypothalamic neuropeptide hypocretin (orexin) 
is involved in the pathogenesis of narcolepsy: (1) a muta- 
tion in the hypocretin receptor 2 gene has been associ- 
ated with canine narcolepsy; (2) hypocretin "knockout" 
mice that are genetically unable to produce this neu- 
ropeptide exhibit behavioral and electrophysiologic fea- 
tures resembling human narcolepsy; and (3) cerebrospinal 
fluid levels of hypocretin are reduced in most patients 
who have narcolepsy with cataplexy. The inheritance 
pattern of narcolepsy in humans is more complex than in 
the canine model. However, almost all narcoleptics with 
cataplexy are positive for HLA DQB1*0602, suggesting 
that an autoimmune process may be responsible. 

Diagnosis 

The diagnostic criteria continue to be a matter of 
debate. Certainly, objective verification of excessive day- 
time somnolence, typically with MSLT mean sleep 
latencies <8 min, is an essential if nonspecific diagnostic 
feature. Other conditions that cause excessive sleepiness, 
such as sleep apnea or chronic sleep deprivation, must 
be rigorously excluded. The other objective diagnostic 
feature of narcolepsy is the presence of REM sleep in at 
least two of the naps during the MSLT. Abnormal regu- 
lation of REM sleep is also manifested by the appear- 
ance of REM sleep immediately or within minutes after 
sleep onset in 50% of narcoleptic patients, a rarity in 
unaffected individuals maintaining a conventional sleep- 
wake schedule. The REM-related symptoms of the classic 
narcolepsy tetrad are variably present. There is increasing 
evidence that narcoleptics with cataplexy (one-half to 
two-thirds of patients) may represent a more homoge- 
neous group than those without this symptom. How- 
ever, a history of cataplexy can be difficult to establish 



reliably. Hypnogogic and hypnopompic hallucinations 165 
and sleep paralysis are often found in nonnarcoleptic 
individuals and may be present in only one-half of nar- 
coleptics. Nocturnal sleep disruption is commonly 
observed in narcolepsy but is also a nonspecific symp- 
tom. Similarly, a history of "automatic behavior" during 
wakefulness (a trancelike state during which simple 
motor behaviors persist) is not specific for narcolepsy 
and serves principally to corroborate the presence of 
daytime somnolence. 



Be 



Treatment: 
NARCOLEPSY 



The treatment of narcolepsy is symptomatic. Somno- oo 
lence is treated with wake-promoting therapeutics. S> 
Modafinil is now the drug of choice, principally because 
it is associated with fewer side effects than older stimu- g 
lants and has a long half-life; 200-400 mg is given as a 3- 
single daily dose. Older drugs such as methylphenidate 33 
(1 mg bid to 20 mg qid) or dextroamphetamine (1 mg 
bid) are still used as alternatives, particularly in refrac- 
tory patients.These latter medications are now available 
in slow-release formulations, extending their duration of 
action and allowing once daily dosing. 

Treatment of the REM-related phenomena cataplexy, 
hypnogogic hallucinations, and sleep paralysis requires 
the potent REM sleep suppression produced by antide- 
pressant medications. The tricyclic antidepressants 
[e.g., protriptyline (10-40 mg/d) and clomipramine 
(25-50 mg/d)] and the selective serotonin reuptake 
inhibitors (SSRIs) [e.g., fluoxetine (10-20 mg/d)] are 
commonly used for this purpose. Efficacy of the antide- 
pressants is limited largely by anticholinergic side effects 
(tricyclics) and by sleep disturbance and sexual dysfunc- 
tion (SSRIs). Alternately, gamma hydroxybutyrate (GHB), 
given at bed time, and 4 h later, is effective in reducing 
daytime cataplectic episodes. Adequate nocturnal sleep 
time and planned daytime naps (when possible) are 
important preventative measures. 



SLEEP APNEA SYNDROMES 

Respiratory dysfunction during sleep is a common, seri- 
ous cause of excessive daytime somnolence as well as of 
disturbed nocturnal sleep. An estimated 2—5 million 
individuals in the United States have a reduction or ces- 
sation of breathing for 10—150 s, from thirty to several 
hundred times every night during sleep. These episodes 
may be due to either an occlusion of the airway (obstructive 
sleep apnea), absence of respiratory effort (central sleep 
apnea), or a combination of these factors (mixed sleep apnea) 
(Fig. 16-3). Failure to recognize and treat these conditions 



166 appropriately may lead to impairment of daytime alert- 
ness, increased risk of sleep-related motor vehicle acci- 
dents, hypertension and other serious cardiovascular 
complications, and increased mortality. Sleep apnea is 
particularly prevalent in overweight men and in the 
elderly, yet it is estimated to remain undiagnosed in 
80—90% of affected individuals. This is unfortunate since 
effective treatments are available. 

PARASOMNIAS 

The term parasomnia refers to abnormal behaviors or 
experiences that arise from or occur during sleep. A 
continuum of parasomnias arises from NREM sleep, 
from brief confusional arousals to sleepwalking and 
night terrors. The presenting complaint is usually related 
to the behavior itself, but the parasomnias can disturb 
sleep continuity or lead to mild impairments in daytime 
alertness. Two main parasomnias occur in REM sleep: 
REM sleep behavior disorder (RBD), which will be 
described later, and nightmare disorder. 



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Sleepwalking (Somnambulism) 

Patients affected by this disorder carry out automatic 
motor activities that range from simple to complex. 
Individuals may walk, urinate inappropriately, eat, or exit 
from the house while remaining only partially aware. 
Full arousal may be difficult, and individuals may rarely 
respond to attempted awakening -with agitation or even 
violence. Sleepwalking arises from stage 3 or 4 NREM 
sleep, usually in the first 2 hours of the night, and is 
most common in children and adolescents, when these 
sleep stages are most robust. Episodes are usually isolated 
but may be recurrent in 1—6% of patients. The cause is 
unknown, though it has a familial basis in roughly one- 
third of cases. 



patient is usually unaware of the problem. The typical 
age of onset is 17—20 years, and spontaneous remission 
usually occurs by 40 years. Sex distribution appears to 
be equal. In many cases, the diagnosis is made during 
dental examination, damage is minor, and no treatment 
is indicated. In more severe cases, treatment with a rub- 
ber tooth guard is necessary to prevent disfiguring tooth 
injury. Stress management or, in some cases, biofeedback 
can be useful when bruxism is a manifestation of psy- 
chological stress. There are anecdotal reports of benefit 
using benzodiazepines. 

Sleep Enuresis 

Bedwetting, like sleepwalking and night terrors, is 
another parasomnia that occurs during sleep in the 
young. Before age 5 or 6, nocturnal enuresis should 
probably be considered a normal feature of develop- 
ment. The condition usually improves spontaneously by 
puberty, has a prevalence in late adolescence of 1—3%, 
and is rare in adulthood. In older patients with enuresis a 
distinction must be made between primary and sec- 
ondary enuresis, the latter being defined as bedwetting 
in patients who have previously been fully continent for 
6—12 months. Treatment of primary enuresis is reserved 
for patients of appropriate age (>5 or 6 years) and con- 
sists of bladder training exercises and behavioral therapy. 
Urologic abnormalities are more common in primary 
enuresis and must be assessed by urologic examination. 
Important causes of secondary enuresis include emo- 
tional disturbances, urinary tract infections or malforma- 
tions, cauda equina lesions, epilepsy, sleep apnea, and 
certain medications. Symptomatic pharmacotherapy is 
usually accomplished with desmopressin (0.2 mg qhs), 
oxybutynin chloride (5—10 mg qhs) or imipramine 
(10-50 mg qhs). 



Sleep Terrors 

This disorder, also called pavor nocturnus, occurs primarily 
in young children during the first several hours after sleep 
onset, in stages 3 and 4 of NREM sleep. The child sud- 
denly screams, exhibiting autonomic arousal with sweat- 
ing, tachycardia, and hyperventilation. The individual may 
be difficult to arouse and rarely recalls the episode on 
awakening in the morning. Parents are usually reassured to 
learn that the condition is self-limited and benign and that 
no specific therapy is indicated. Both sleep terrors and 
sleepwalking represent abnormalities of arousal. In con- 
trast, nightmares occur during REM sleep and cause full 
arousal, with intact memory for the unpleasant episode. 

Sleep Bruxism 

Bruxism is an involuntary, forceful grinding of teeth 
during sleep that affects 10—20% of the population. The 



Miscellaneous Parasomnias 

Other clinical entities may be characterized as a para- 
somnia or a sleep-related movement disorder in that 
they occur selectively during sleep and are associated 
with some degree of sleep disruption. Examples include 
jactatio capitis noctuma (nocturnal headbanging, rhythmic 
movement disorder), confusional arousals, sleep-related 
eating disorder, and nocturnal leg cramps. 

REM Sleep Behavior Disorder (RBD) 

RBD is a rare condition that is distinct from other para- 
somnias in that it occurs during REM sleep. It primarily 
afflicts men of middle age or older, many of whom have 
an existing, or developing, neurologic disease. Approxi- 
mately one-half of patients with RBD will develop 
Parkinson's disease (Chap. 24) within 10—20 years. Pre- 
senting symptoms consist of agitated or violent behavior 



during sleep, as reported by a bed partner. In contrast to 
typical somnambulism, injury to the patient or bed part- 
ner is not uncommon, and, upon awakening, the patient 
reports vivid, often unpleasant, dream imagery. The 
principal differential diagnosis is nocturnal seizures, 
which can be excluded with polysomnography. In RBD, 
seizure activity is absent on the EEG, and disinhibition 
of the usual motor atonia is observed in the EMG dur- 
ing REM sleep, at times associated with complex motor 
behaviors. The pathogenesis is unclear, but damage to 
brainstem areas mediating descending motor inhibition 
during REM sleep may be responsible. In support of this 
hypothesis are the remarkable similarities between RBD 
and the sleep of animals with bilateral lesions of the pon- 
tine tegmentum in areas controlling REM sleep motor 
inhibition. Treatment with clonazepam (0.5—1.0 mg qhs) 
provides sustained improvement in almost all reported 
cases. 



CIRCADIAN RHYTHM SLEEP 
DISORDERS 

A subset of patients presenting with either insomnia or 
hypersomnia may have a disorder of sleep timing rather 
than sleep generation. Disorders of sleep timing can be 
either organic (i.e., due to an intrinsic defect in the cir- 
cadian pacemaker or its input from entraining stimuli) 
or environmental (i.e., due to a disruption of exposure to 
entraining stimuli from the environment). Regardless of 
etiology, the symptoms reflect the influence of the 
underlying circadian pacemaker on sleep-wake function. 
Thus, effective therapeutic approaches should aim to 
entrain the oscillator at an appropriate phase. 

Jet Lag Disorder 

More than 60 million persons experience transmeridian 
air travel annually, which is often associated with exces- 
sive daytime sleepiness, sleep onset insomnia, and fre- 
quent arousals from sleep, particularly in the latter half of 
the night. Gastrointestinal discomfort is common. The 
syndrome is transient, typically lasting 2—14 d depending 
on the number of time zones crossed, the direction of 
travel, and the traveler's age and phase-shifting capacity. 
Travelers who spend more time outdoors reportedly 
adapt more quickly than those who remain in hotel 
rooms, presumably due to bright (outdoor) light expo- 
sure. Avoidance of antecedent sleep loss and obtaining 
nap sleep on the afternoon prior to overnight travel 
greatly reduces the difficulty of extended wakefulness. 
Laboratory studies suggest that sub-milligram doses of 
the pineal hormone melatonin can enhance sleep effi- 
ciency, but only if taken -when endogenous melatonin 
concentrations are low (i.e., during biologic daytime), 
and that melatonin may induce phase shifts in human 



o 

O 



rhythms. A large-scale clinical trial evaluating the safety 167 
and efficacy of melatonin as a treatment for jet lag disor- 
der and other circadian sleep disorders is needed. 

Shift-Work Disorder 

More than 7 million workers in the United States regu- 
larly work at night, either on a permanent or rotating 
schedule. In addition, each week millions more elect to 
remain awake at night to meet deadlines, drive long dis- 
tances, or participate in recreational activities. This 
results in both sleep loss and misalignment of the circa- 
dian rhythm with respect to the sleep- wake cycle. 

Studies of regular night-shift workers indicate that 
the circadian timing system usually fails to adapt success- 
fully to such inverted schedules. This leads to a misalign- 
ment between the desired work-rest schedule and the 
output of the pacemaker and in disturbed daytime sleep 
in most individuals. Sleep deprivation, increased length 
of time awake prior to work, and misalignment of circa- 
dian phase produce decreased alertness and perfor- 
mance, increased reaction time, and increased risk of 
performance lapses, thereby resulting in greater safety 
hazards among night workers and other sleep-deprived 
individuals. Sleep disturbance nearly doubles the risk of 
a fatal work accident. Additional problems include 
higher rates of cancer and of cardiac, gastrointestinal, and 
reproductive disorders in chronic night-shift workers. 

Sleep onset is associated with marked attenuation in 
perception of both auditory and visual stimuli and lapses 
of consciousness. The sleepy individual may thus attempt to 
perform routine and familiar motor tasks during the transi- 
tion state between wakefulness and sleep (stage 1 sleep) 
in the absence of adequate processing of sensory input 
from the environment. Motor vehicle operators are espe- 
cially vulnerable to sleep-related accidents since the sleep- 
deprived driver or operator often fails to heed the warning 
signs of fatigue. Such attempts to override the powerful 
biologic drive for sleep by the sheer force of will can yield 
a catastrophic outcome when sleep processes intrude 
involuntarily upon the waking brain. Such sleep-related 
attentional failures typically last only seconds but are 
known on occasion to persist for longer durations. These 
frequent brief intrusions of stage 1 sleep into behavioral 
wakefulness are a major component of the impaired psy- 
chomotor performance seen with sleepiness. There is a 
significant increase in the risk of sleep-related, fatal-to- 
the-driver highway crashes in the early morning and late 
afternoon hours, coincident with bimodal peaks in the 
daily rhythm of sleep tendency. 

Medical housestaff constitute another group of work- 
ers at risk for accidents and other adverse consequences 
of lack of sleep and misalignment of the circadian 
rhythm. Recent research has demonstrated that the 
practice of scheduling interns and residents to work 
shifts of 30 consecutive hours both doubles the risk of 



168 



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attentional failures among intensive care unit interns 
working at night and significantly increases the risk of 
serious medical errors in intensive care units. Moreover, 
working for >24 h consecutively increases the risk of 
needlestick injuries and more than doubles the risk of 
motor vehicle crashes on the commute home. Some 
20% of hospital interns report making a fatigue-related 
mistake that injured a patient, and 5% admit making a 
mistake that results in the death of a patient. 

From 5—10% of individuals scheduled to work at 
night or in the early morning hours have much greater 
than average difficulties remaining awake during night 
work and sleeping during the day; these individuals are 
diagnosed with chronic and severe shift-work disorder 
(SWD). Patients with this disorder have a level of exces- 
sive sleepiness during night work and insomnia during 
day sleep that the physician judges to be clinically signif- 
icant; the condition is associated with an increased risk 
of sleep-related accidents and with some of the illnesses 
associated with night-shift work. Patients with chronic 
and severe SWD are profoundly sleepy at night. In fact, 
their sleep latencies during night work average just 2 min, 
comparable to mean sleep latency durations of patients 
with narcolepsy or severe daytime sleep apnea. 



Be 



Treatment: 
SHIFT-WORK DISORDER 



Caffeine is frequently used to promote wakefulness. 
However, it cannot forestall sleep indefinitely, and it 
does not shield users from sleep-related performance 
lapses. Postural changes, exercise, and strategic place- 
ment of nap opportunities can sometimes temporarily 
reduce the risk of fatigue-related performance lapses. 
Properly timed exposure to bright light can facilitate 
rapid adaptation to night-shift work. 

While many techniques (e.g., light treatment) used to 
facilitate adaptation to night shift work may help 
patients with this disorder, modafinil is the only thera- 
peutic intervention that has ever been evaluated as a 
treatment for this specific patient population. Modafinil 
(200 mg, taken 30-60 min before the start of each night 
shift) is approved by the U.S. Food and Drug Administra- 
tion as a treatment for the excessive sleepiness during 
night work in patients with SWD. Although treatment 
with modafinil significantly increases sleep latency and 
reduces the risk of lapses of attention during night 
work, SWD patients remain excessively sleepy at night, 
even while being treated with modafinil. 

Safety programs should promote education about 
sleep and increase awareness of the hazards associated 
with night work. The goal should be to minimize both 
sleep deprivation and circadian disruption. Work sched- 
ules should be designed to minimize: (1) exposure to 



night work, (2) the frequency of shift rotation so that 
shifts do not rotate more than once every 2-3 weeks, (3) 
the number of consecutive night shifts, and (4) the 
duration of night shifts. Shift durations of >16 h should 
be universally recognized as increasing the risk of sleep- 
related errors and performance lapses to a level that is 
unacceptable in nonemergency circumstances. 



Delayed Sleep Phase Disorder 

Delayed sleep phase disorder is characterized by: (1) 
reported sleep onset and wake times intractably later 
than desired, (2) actual sleep times at nearly the same 
clock hours daily, and (3) essentially normal all-night 
polysomnography except for delayed sleep onset. 
Patients exhibit an abnormally delayed endogenous cir- 
cadian phase, with the temperature minimum during 
the constant routine occurring later than normal. This 
delayed phase could be due to: (1) an abnormally long, 
genetically determined intrinsic period of the endoge- 
nous circadian pacemaker; (2) an abnormally reduced 
phase-advancing capacity of the pacemaker; or (3) an 
irregular prior sleep-wake schedule, characterized by 
frequent nights when the patient chooses to remain 
awake well past midnight (for social, school, or work 
reasons). In most cases, it is difficult to distinguish 
among these factors, since patients with an abnormally 
long intrinsic period are more likely to "choose" such 
late-night activities because they are unable to sleep at 
that time. Patients tend to be young adults. This self- 
perpetuating condition can persist for years and does 
not usually respond to attempts to reestablish normal 
bedtime hours. Treatment methods involving bright- 
light phototherapy during the morning hours or mela- 
tonin administration in the evening hours show promise 
in these patients, although the relapse rate is high. 

Advanced Sleep Phase Disorder 

Advanced sleep phase disorder (ASPD) is the converse 
of the delayed sleep phase syndrome. Most commonly, 
this syndrome occurs in older people, 15% of whom 
report that they cannot sleep past 5 a.m., with twice that 
number complaining that they wake up too early at least 
several times per week. Patients -with ASPD experience 
excessive daytime sleepiness during the evening hours, 
when they have great difficulty remaining awake, even 
in social settings. Typically, patients awaken from 3—5 A.M. 
each day, often several hours before their desired wake 
times. In addition to age-related ASPD, an early-onset 
familial variant of this condition has also been reported. 
In one such family, autosomal dominant ASPD was due 
to a missense mutation in a circadian clock component 
(PER2, as shown in Fig. 16-2) that altered the circadian 



period. Patients with ASPD may benefit from bright- 
light phototherapy during the evening hours, designed 
to reset the circadian pacemaker to a later hour. 

Non-24-Hour Sleep-Wake Disorder 

This condition can occur when the maximal phase- 
advancing capacity of the circadian pacemaker is not ade- 
quate to accommodate the difference between the 24-h 
geophysical day and the intrinsic period of the pacemaker 
in the patient. Alternatively patients' self-selected exposure 
to artificial light may drive the circadian pacemaker to a 
>24-h schedule. Affected patients are not able to maintain 
a stable phase relationship between the output of the 
pacemaker and the 24-h day. Such patients typically pre- 
sent with an incremental pattern of successive delays in 
sleep onsets and wake times, progressing in and out of 
phase with local time. When the patient's endogenous 
rhythms are out of phase with the local environment, 
insomnia coexists with excessive daytime sleepiness. Con- 
versely, when the endogenous rhythms are in phase with 
the local environment, symptoms remit. The intervals 
between symptomatic periods may last several weeks to 
several months. Blind individuals unable to perceive light 
are particularly susceptible to this disorder. Nightly low- 
dose (0.5 mg) melatonin administration has been reported 
to improve sleep and, in some cases, to induce synchro- 
nization of the circadian pacemaker. 

MEDICAL IMPLICATIONS OF CIRCADIAN 
RHYTHMICITY 

Prominent circadian variations have been reported in 
the incidence of acute myocardial infarction, sudden 
cardiac death, and stroke, the leading causes of death in 
the United States. Platelet aggregability is increased after 
arising in the early morning hours, coincident with the 
peak incidence of these cardiovascular events. A better 



understanding of the possible role of circadian rhythmic- 
ity in the acute destabilization of a chronic condition 
such as atherosclerotic disease could improve the under- 
standing of the pathophysiology. 

Diagnostic and therapeutic procedures may also be 
affected by the time of day at which data are collected. 
Examples include blood pressure, body temperature, the 
dexamethasone suppression test, and plasma Cortisol levels. 
The timing of chemotherapy administration has been 
reported to have an effect on the outcome of treatment. 
Few physicians realize the extent to which routine mea- 
sures are affected by the time (or sleep/wake state) when 
the measurement is made. 

In addition, both the toxicity and effectiveness of 
drugs can vary during the day. For example, more than a 
fivefold difference has been observed in mortality rates 
following administration of toxic agents to experimental 
animals at different times of day. Anesthetic agents are 
particularly sensitive to time-of-day effects. Finally, the 
physician must be increasingly aware of the public 
health risks associated with the ever-increasing demands 
made by the duty-rest-recreation schedules in our 
round-the-clock society. 



FURTHER READINGS 

BLOOM HG et al: Evidence-based recommendations for the assess- 
ment and management of sleep disorders in older persons. J Am 
GeriatrSoc 57:761,2009 

BRADLEY TD, FLORAS JS: Obstructive sleep apnoea and its cardiovas- 
cular consequences. Lancet 373:82, 2009 

FLEMONS WW: Clinical practice. Obstructive sleep apnea. N Engl J 
Med 347:498, 2002 

SCAMMELL TE: The neurobiology, diagnosis, and treatment of nar- 
colepsy. Ann Neurol 53:154, 2003 

SlLBER MH: Clinical practice. Chronic insomnia. N Engl J Med 
353:803, 2005 

WISE MS et al: Treatment of narcolepsy and other hypersomnias of 
central origin. Sleep 30: 1712, 2009 



169 



rD 
rD 



rD 




Jonathan C. Horton 



The Human Visual System 170 

Clinical Assessment of Visual Function 1 71 

Refractive State 1 71 

Visual Acuity 1 71 

Pupils 172 

Eye Movements and Alignment 1 73 

Stereopsis 1 73 

Color Vision 1 73 

Visual Fields 1 74 



Disorders 1 75 

Red or Painful Eye 1 75 

Transient or Sudden Visual Loss 1 78 

Chronic Visual Loss 1 84 

Proptosis 1 86 

Ptosis 187 

Double Vision (Diplopia) 1 88 

Further Readings 1 92 



THE HUMAN VISUAL SYSTEM 

The visual system provides a supremely efficient means 
for the rapid assimilation of information from the envi- 
ronment to aid in the guidance of behavior. The act of 
seeing begins with the capture of images focused by the 
cornea and lens upon a light-sensitive membrane in the 
back of the eye, called the retina. The retina is actually 
part of the brain, banished to the periphery to serve as a 
transducer for the conversion of patterns of light energy 
into neuronal signals. Light is absorbed by photopigment 
in two types of receptors: rods and cones. In the human 
retina there are 100 million rods and 5 million cones. 
The rods operate in dim (scotopic) illumination. The 
cones function under daylight (photopic) conditions. 
The cone system is specialized for color perception and 
high spatial resolution. The majority of cones are located 
within the macula, the portion of the retina serving the 
central 10° of vision. In the middle of the macula a small 
pit termed the fovea, packed exclusively with cones, pro- 
vides best visual acuity. 

Photoreceptors hyperpolarize in response to light, acti- 
vating bipolar, amacrine, and horizontal cells in the inner 
nuclear layer. After processing of photoreceptor responses 
by this complex retinal circuit, the flow of sensory infor- 
mation ultimately converges upon a final common path- 
way: the ganglion cells. These cells translate the visual image 



impinging upon the retina into a continuously varying bar- 
rage of action potentials that propagates along the primary 
optic pathway to visual centers within the brain. There are 
a million ganglion cells in each retina, and hence a million 
fibers in each optic nerve. 

Ganglion cell axons sweep along the inner surface of 
the retina in the nerve fiber layer, exit the eye at the optic 
disc, and travel through the optic nerve, optic chiasm, and 
optic tract to reach targets in the brain. The majority of 
fibers synapse upon cells in the lateral geniculate body, a 
thalamic relay station. Cells in the lateral geniculate body 
project in turn to the primary visual cortex. This massive 
afferent retinogeniculocortical sensory pathway provides 
the neural substrate for visual perception. Although the 
lateral geniculate body is the main target of the retina, 
separate classes of ganglion cells project to other subcorti- 
cal visual nuclei involved in different functions. Ganglion 
cells that mediate pupillary constriction and circadian 
rhythms are light sensitive, owing to a novel visual pig- 
ment, melanopsin. Pupil responses are mediated by input 
to the pretectal olivary nuclei in the midbrain. The pre- 
tectal nuclei send their output to the Edinger-Westphal 
nuclei, which in turn provide parasympathetic innerva- 
tion to the iris sphincter via an interneuron in the ciliary 
ganglion. Circadian rhythms are timed by a retinal projec- 
tion to the suprachiasmatic nucleus. Visual orientation and 
eye movements are served by retinal input to the superior 



170 



colliculus. Gaze stabilization and optokinetic reflexes are 
governed by a group of small retinal targets known col- 
lectively as the brainstem accessory optic system. 

The eyes must be rotated constantly within their 
orbits to place and maintain targets of visual interest 
upon the fovea. This activity, called foveation, or looking, 
is governed by an elaborate efferent motor system. Each 
eye is moved by six extraocular muscles, supplied by cra- 
nial nerves from the oculomotor (III), trochlear (IV), 
and abducens (VI) nuclei. Activity in these ocular motor 
nuclei is coordinated by pontine and midbrain mecha- 
nisms for smooth pursuit, saccades, and gaze stabilization 
during head and body movements. Large regions of the 
frontal and parietooccipital cortex control these brain- 
stem eye movement centers by providing descending 
supranuclear input. 



CLINICAL ASSESSMENT OF VISUAL 
FUNCTION 

REFRACTIVE STATE 

In approaching the patient with reduced vision, the first 
step is to decide whether refractive error is responsible. In 
emmetropia, parallel rays from infinity are focused perfectly 
upon the retina. Sadly, this condition is enjoyed by only a 
minority of the population. In myopia, the globe is too 
long, and light rays come to a focal point in front of the 
retina. Near objects can be seen clearly, but distant objects 
require a diverging lens in front of the eye. In hyperopia, 
the globe is too short, and hence a converging lens is used 
to supplement the refractive power of the eye. In astigma- 
tism, the corneal surface is not perfectly spherical, necessi- 
tating a cylindrical corrective lens. In recent years it has 
become possible to correct refractive error with the 
excimer laser by performing LASIK (laser in situ ker- 
atomileusis) to alter the curvature of the cornea. 

With the onset of middle age, presbyopia develops as 
the lens within the eye becomes unable to increase its 
refractive power to accommodate upon near objects. To 
compensate for presbyopia, the emmetropic patient must 
use reading glasses. The patient already wearing glasses 
for distance correction usually switches to bifocals. The 
only exception is the myopic patient, who may achieve 
clear vision at near simply by removing glasses containing 
the distance prescription. 

Refractive errors usually develop slowly and remain 
stable after adolescence, except in unusual circum- 
stances. For example, the acute onset of diabetes mellitus 
can produce sudden myopia because of lens edema 
induced by hyperglycemia. Testing vision through a pin- 
hole aperture is a useful way to screen quickly for 
refractive error. If the visual acuity is better through a 
pinhole than with the unaided eye, the patient needs a 
refraction to obtain best corrected visual acuity. 



VISUAL ACUITY 171 

The Snellen chart is used to test acuity at a distance of 
6 m (20 ft). For convenience, a scale version of the Snellen 
chart, called the Rosenbaum card, is held at 36 cm (14 in) 
from the patient (Fig. 17-1). All subjects should be able 
to read the 6/6 m (20/20 ft) line with each eye using 
their refractive correction, if any. Patients who need read- 
ing glasses because of presbyopia must wear them for 
accurate testing with the Rosenbaum card. If 6/6 (20/20) 



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vision for each eye separately with and without 
glasses. Presbyopic patients should read thru bifocal 
segment. Check myopes with glasses only. 



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PUPIL GAUGE (mm.) 

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FIGURE 17-1 

The Rosenbaum card is a miniature, scale version of the 
Snellen chart for testing visual acuity at near. When the 
visual acuity is recorded, the Snellen distance equivalent 
should bear a notation indicating that vision was tested at 
near, not at 6 m (20 ft), or else the Jaeger number system 
should be used to report the acuity. 



172 



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acuity is not present in each eye, the deficiency in vision 
must be explained. If worse than 6/240 (20/800), acuity 
should be recorded in terms of counting fingers, hand 
motions, light perception, or no light perception. Legal 
blindness is defined by the Internal Revenue Service as a 
best corrected acuity of 6/60 (20/200) or less in the bet- 
ter eye, or a binocular visual field subtending 20° or less. 
For driving the laws vary by state, but most require a 
corrected acuity of 6/12 (20/40) in at least one eye for 
unrestricted privileges. Patients with a homonymous 
hemianopia should not drive. 

PUPILS 

The pupils should be tested individually in dim light 
with the patient fixating on a distant target. If they 
respond briskly to light, there is no need to check the 
near response, because isolated loss of constriction (mio- 
sis) to accommodation does not occur. For this reason, 
the ubiquitous abbreviation PERRLA (pupils equal, 
round, and reactive to light and accommodation) implies 
a wasted effort with the last step. However, it is impor- 
tant to test the near response if the light response is poor or 
absent. Light-near dissociation occurs with neurosyphilis 
(Argyll Robertson pupil), lesions of the dorsal midbrain 
(obstructive hydrocephalus, pineal region tumors), and 
after aberrant regeneration (oculomotor nerve palsy, Adie's 
tonic pupil). 

An eye with no light perception has no pupillary 
response to direct light stimulation. If the retina or optic 
nerve is only partially injured, the direct pupillary response 
will be weaker than the consensual pupillary response 
evoked by shining a light into the other eye. This relative 
afferent pupillary defect (Marcus Gunn pupil) can be 
elicited with the swinging flashlight test (Fig. 17-2). It 
is an extremely useful sign in retrobulbar optic neuritis 
and other optic nerve diseases, where it may be the sole 
objective evidence for disease. 

Subtle inequality in pupil size, up to 0.5 mm, is a 
fairly common finding in normal persons. The diagnosis 
of essential or physiologic anisocoria is secure as long as 
the relative pupil asymmetry remains constant as ambi- 
ent lighting varies. Anisocoria that increases in dim light 
indicates a sympathetic paresis of the iris dilator muscle. 
The triad of miosis with ipsilateral ptosis and anhidrosis 
constitutes Horner's syndrome, although anhidrosis is an 
inconstant feature. Brainstem stroke, carotid dissection, 
or neoplasm impinging upon the sympathetic chain are 
occasionally identified as the cause of Horner's syn- 
drome, but most cases are idiopathic. 

Anisocoria that increases in bright light suggests a 
parasympathetic palsy. The first concern is an oculomotor 
nerve paresis. This possibility is excluded if the eye move- 
ments are full and the patient has no ptosis or diplopia. 
Acute pupillary dilation (mydriasis) can occur from damage 
to the ciliary ganglion in the orbit. Common mechanisms 




FIGURE 17-2 

Demonstration of a relative afferent pupil defect (Marcus 
Gunn pupil) in the left eye, done with the patient fixating 
upon a distant target. A With dim background lighting, the 
pupils are equal and relatively large. B. Shining a flashlight 
into the right eye evokes equal, strong constriction of both 
pupils. C. Swinging the flashlight over to the damaged left 
eye causes dilation of both pupils, although they remain 
smaller than in A. Swinging the flashlight back over to the 
healthy right eye would result in symmetric constriction back 
to the appearance shown in B. Note that the pupils always 
remain equal; the damage to the left retina/optic nerve is 
revealed by weaker bilateral pupil constriction to a flashlight 
in the left eye compared with the right eye. (From P Levatin, 
Arch Ophthalmol 62:768, 1959.) 



are infection (herpes zoster, influenza), trauma (blunt, pen- 
etrating, surgical), or ischemia (diabetes, temporal arteritis). 
After denervation of the iris sphincter the pupil does not 
respond well to light, but the response to near is often 
relatively intact. When the near stimulus is removed, the 
pupil redilates very slowly compared with the normal pupil, 
hence the term tonic pupil. In Adie's syndrome, a tonic pupil 
occurs in conjunction with weak or absent tendon reflexes 
in the lower extremities. This benign disorder, which occurs 



predominantly in healthy young women, is assumed to 
represent a mild dysautonomia. Tonic pupils are also asso- 
ciated with Shy-Drager syndrome, segmental hypohidrosis, 
diabetes, and amyloidosis. Occasionally, a tonic pupil is dis- 
covered incidentally in an otherwise completely normal, 
asymptomatic individual. The diagnosis is confirmed by 
placing a drop of dilute (0.125%) pilocarpine into each 
eye. Denervation hypersensitivity produces pupillary con- 
striction in a tonic pupil, whereas the normal pupil shows 
no response. Pharmacologic dilation from accidental or 
deliberate instillation of anticholinergic agents (atropine, 
scopolamine drops) into the eye can also produce pupillary 
mydriasis. In this situation, normal strength (1%) pilo- 
carpine causes no constriction. 

Both pupils are affected equally by systemic medica- 
tions. They are small with narcotic use (morphine, 
heroin) and large with anticholinergics (scopolamine). 
Parasympathetic agents (pilocarpine, demecarium bro- 
mide) used to treat glaucoma produce miosis. In any 
patient with an unexplained pupillary abnormality, a 
slit-lamp examination is helpful to exclude surgical 
trauma to the iris, an occult foreign body, perforating 
injury, intraocular inflammation, adhesions (synechia), 
angle-closure glaucoma, and iris sphincter rupture from 
blunt trauma. 

EYE MOVEMENTS AND ALIGNMENT 

Eye movements are tested by asking the patient with 
both eyes open to pursue a small target such as a penlight 
into the cardinal fields of gaze. Normal ocular versions 
are smooth, symmetric, full, and maintained in all direc- 
tions without nystagmus. Saccades, or quick refixation 
eye movements, are assessed by having the patient look 
back and forth between two stationary targets. The eyes 
should move rapidly and accurately in a single jump to 
their target. Ocular alignment can be judged by holding 
a penlight directly in front of the patient at about 1 m. If 
the eyes are straight, the corneal light reflex will be cen- 
tered in the middle of each pupil. To test eye alignment 
more precisely, the cover test is useful. The patient is 
instructed to gaze upon a small fixation target in the dis- 
tance. One eye is covered suddenly while observing the 
second eye. If the second eye shifts to fixate upon the 
target, it was misaligned. If it does not move, the first eye 
is uncovered and the test is repeated on the second eye. If 
neither eye moves, the eyes are aligned orthotropically If 
the eyes are orthotropic in primary gaze but the patient 
complains of diplopia, the cover test should be per- 
formed with the head tilted or turned in whatever direc- 
tion elicits diplopia. With practice the examiner can 
detect an ocular deviation (heterotropia) as small as 1—2° 
with the cover test. Deviations can be measured by plac- 
ing prisms in front of the misaligned eye to determine 
the power required to neutralize the fixation shift evoked 
by covering the other eye. 



STEREOPSIS 173 

Stereoacuity is determined by presenting targets with reti- 
nal disparity separately to each eye using polarized images. 
The most popular office tests measure a range of thresh- 
olds from 800—40 seconds of arc. Normal stereoacuity is 
40 seconds of arc. If a patient achieves this level of 
stereoacuity, one is assured that the eyes are aligned 
orthotropically and that vision is intact in each eye. Ran- 
dom dot stereograms have no monocular depth cues and 
provide an excellent screening test for strabismus and 
amblyopia in children. 



COLOR VISION 

The retina contains three classes of cones, with visual 
pigments of differing peak spectral sensitivity: red (560 nm) , g 
green (530 nm), and blue (430 nm).The red and green o- 
cone pigments are encoded on the X chromosome; the C3 
blue cone pigment on chromosome 7. Mutations of the S, 
blue cone pigment are exceedingly rare. Mutations of j^- 
the red and green pigments cause congenital X-linked § 
color blindness in 8% of men. Affected individuals are 
not truly color blind; rather, they differ from normal 
subjects in how they perceive color and how they com- 
bine primary monochromatic lights to match a given 
color. Anomalous trichromats have three cone types, 
but a mutation in one cone pigment (usually red or 
green) causes a shift in peak spectral sensitivity, alter- 
ing the proportion of primary colors required to 
achieve a color match. Dichromats have only two 
cone types and will therefore accept a color match 
based upon only two primary colors. Anomalous 
trichromats and dichromats have 6/6 (20/20) visual 
acuity, but their hue discrimination is impaired. Ishi- 
hara color plates can be used to detect red-green color 
blindness. The test plates contain a hidden number, 
visible only to subjects with color confusion from red- 
green color blindness. Because color blindness is almost 
exclusively X-linked, it is worth screening only male 
children. 

The Ishihara plates are often used to detect acquired 
defects in color vision, although they are intended as a 
screening test for congenital color blindness. Acquired 
defects in color vision frequently result from disease of 
the macula or optic nerve. For example, patients with a 
history of optic neuritis often complain of color desat- 
uration long after their visual acuity has returned to 
normal. Color blindness can also occur from bilateral 
strokes involving the ventral portion of the occipital 
lobe (cerebral achromatopsia). Such patients can per- 
ceive only shades of gray and may also have difficulty 
recognizing faces (prosopagnosia) . Infarcts of the domi- 
nant occipital lobe sometimes give rise to color 
anomia. Affected patients can discriminate colors, but 
they cannot name them. 



174 VISUAL FIELDS 

Vision can be impaired by damage to the visual system 
anywhere from the eyes to the occipital lobes. One can 
localize the site of the lesion with considerable accuracy 
by mapping the visual field deficit by finger confronta- 
tion and then correlating it with the topographic 
anatomy of the visual pathway (Fig. 17-3). Quantitative 
visual field mapping is performed by computer-driven 
perimeters (Humphrey Octopus) that present a target of 
variable intensity at fixed positions in the visual field 



(Fig. 17 -3 A). By generating an automated printout of 
light thresholds, these static perimeters provide a sensi- 
tive means of detecting scotomas in the visual field. 
They are exceedingly useful for serial assessment of 
visual function in chronic diseases such as glaucoma or 
pseudotumor cerebri. 

The crux of visual field analysis is to decide whether 
a lesion is before, at, or behind the optic chiasm. If a 
scotoma is confined to one eye, it must be due to a 
lesion anterior to the chiasm, involving either the optic 



Monocular Prechiasmal Field Defects: 

fi — ^- 30 ' tHi* * ' 3D ' 

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Normal Reld Central Scotoma Nerve-Fiber Bundle 

Right Eye (Arcuate ) Scotoma 




fin 



Ceco-central 
Scotoma 



Enlarged Blind-Spot 
with Peripheral Constriction 



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Binocular Chiasmal or 
Postchiasmal Field Defects: 

(Left eye) (Righieye) 




Homonymous Hcmianopia 



0t- A 



Superior Quadrantanopia 

t£r I: v . Sth 



Inferior Quadraniaiiopia 

Homonymous Hcmianopia 
with Macular Sparing 




lateral 

•Geniculate Body 



Optic Radiations 



Primary Visual Cortex 



FIGURE 17-3 

Ventral view of the brain, correlating patterns of visual 
field loss with the sites of lesions in the visual pathway. 

The visual fields overlap partially, creating 120° of central 
binocular field flanked by a 40° monocular crescent on either 
side. The visual field maps in this figure were done with a 
computer-driven perimeter (Humphrey Instruments, Carl Zeiss, 
Inc.). It plots the retinal sensitivity to light in the central 30° 



using a gray scale format. Areas of visual field loss are 
shown in black. The examples of common monocular, 
prechiasmal field defects are all shown for the right eye. By 
convention, the visual fields are always recorded with the left 
eye's field on the left, and the right eye's field on the right, 
just as the patient sees the world. 



nerve or retina. Retinal lesions produce scotomas that 
correspond optically to their location in the fundus. For 
example, a superior-nasal retinal detachment results in 
an inferior-temporal field cut. Damage to the macula 
causes a central scotoma (Fig. 17-3B). 

Optic nerve disease produces characteristic patterns 
of visual field loss. Glaucoma selectively destroys axons 
that enter the superotemporal or inferotemporal poles of 
the optic disc, resulting in arcuate scotomas shaped like a 
Turkish scimitar, which emanate from the blind spot and 
curve around fixation to end flat against the horizontal 
meridian (Fig. 1 7-3 Q . This type of field defect mirrors 
the arrangement of the nerve fiber layer in the temporal 
retina. Arcuate or nerve fiber layer scotomas also occur 
from optic neuritis, ischemic optic neuropathy, optic 
disc drusen, and branch retinal artery or vein occlusion. 

Damage to the entire upper or lower pole of the 
optic disc causes an altitudinal field cut that follows the 
horizontal meridian (Fig. 17-3D).This pattern of visual 
field loss is typical of ischemic optic neuropathy but also 
occurs from retinal vascular occlusion, advanced glau- 
coma, and optic neuritis. 

About half the fibers in the optic nerve originate 
from ganglion cells serving the macula. Damage to 
papillomacular fibers causes a cecocentral scotoma 
encompassing the blind spot and macula (Fig. 17-3 E). If 
the damage is irreversible, pallor eventually appears in 
the temporal portion of the optic disc. Temporal pallor 
from a cecocentral scotoma may develop in optic neuri- 
tis, nutritional optic neuropathy, toxic optic neuropathy, 
Leber's hereditary optic neuropathy, and compressive 
optic neuropathy. It is worth mentioning that the tem- 
poral side of the optic disc is slightly more pale than the 
nasal side in most normal individuals. Therefore, it can 
sometimes be difficult to decide whether the temporal 
pallor visible on fundus examination represents a patho- 
logic change. Pallor of the nasal rim of the optic disc is a 
less equivocal sign of optic atrophy. 

At the optic chiasm, fibers from nasal ganglion cells 
decussate into the contralateral optic tract. Crossed fibers 
are damaged more by compression than uncrossed fibers. 
As a result, mass lesions of the sellar region cause a tempo- 
ral hemianopia in each eye. Tumors anterior to the optic 
chiasm, such as meningiomas of the tuberculum sella, pro- 
duce a junctional scotoma characterized by an optic neu- 
ropathy in one eye and a superior-temporal field cut in 
the other eye (Fig. 17-3G). More symmetric compression 
of the optic chiasm by a pituitary adenoma, meningioma, 
craniopharyngioma, glioma, or aneurysm results in a 
bitemporal hemianopia (Fig. 17-3fJ).The insidious devel- 
opment of a bitemporal hemianopia often goes unnoticed 
by the patient and will escape detection by the physician 
unless each eye is tested separately. 

It is difficult to localize a postchiasmal lesion accurately, 
because injury anywhere in the optic tract, lateral genicu- 
late body, optic radiations, or visual cortex can produce a 



homonymous hemianopia, i.e., a temporal hemifield defect 
in the contralateral eye and a matching nasal hemifield 
defect in the ipsilateral eye (Fig. 17-3J). A unilateral 
postchiasmal lesion leaves the visual acuity in each eye 
unaffected, although the patient may read the letters on 
only the left or right half of the eye chart. Lesions of the 
optic radiations tend to cause poorly matched or 
incongruous field defects in each eye. Damage to the optic 
radiations in the temporal lobe (Meyer's loop) produces a 
superior quadrantic homonymous hemianopia (Fig. 17-3/), 
whereas injury to the optic radiations in the parietal lobe 
results in an inferior quadrantic homonymous hemianopia 
(Fig. 17-3K"). Lesions of the primary visual cortex give rise 
to dense, congruous hemianopic field defects. Occlusion 
of the posterior cerebral artery supplying the occipital lobe 
is a frequent cause of total homonymous hemianopia. 
Some patients with hemianopia after occipital stroke have 
macular sparing, because the macular representation at the 
tip of the occipital lobe is supplied by collaterals from 
the middle cerebral artery (Fig. 17-3L). Destruction of 
both occipital lobes produces cortical blindness. This con- 
dition can be distinguished from bilateral prechiasmal 
visual loss by noting that the pupil responses and optic 
fundi remain normal. 



DISORDERS 

RED OR PAINFUL EYE 

Corneal Abrasions 

These are seen best by placing a drop of fluorescein in 
the eye and looking with the slit lamp using a cobalt- 
blue light. A penlight with a blue filter will suffice if no 
slit lamp is available. Damage to the corneal epithelium is 
revealed by yellow fluorescence of the exposed basement 
membrane underlying the epithelium. It is important to 
check for foreign bodies. To search the conjunctival for- 
nices, the lower lid should be pulled down and the 
upper lid everted. A foreign body can be removed with 
a moistened cotton-tipped applicator after placing a 
drop of topical anesthetic, such as proparacaine, in the 
eye. Alternatively, it may be possible to flush the foreign 
body from the eye by irrigating copiously with saline or 
artificial tears. If the corneal epithelium has been 
abraded, antibiotic ointment and a patch should be applied 
to the eye. A drop of an intermediate-acting cycloplegic, 
such as cyclopentolate hydrochloride 1%, helps to reduce 
pain by relaxing the ciliary body. The eye should be reex- 
amined the next day. Minor abrasions may not require 
patching and cycloplegia. 

Subconjunctival Hemorrhage 

This results from rupture of small vessels bridging the 
potential space between the episclera and conjunctiva. 



175 






ST 
o' 



1 76 Blood dissecting into this space can produce a spectacu- 
lar red eye, but vision is not affected and the hemorrhage 
resolves without treatment. Subconjunctival hemorrhage 
is usually spontaneous but can occur from blunt trauma, 
eye rubbing, or vigorous coughing. Occasionally it is a 
clue to an underlying bleeding disorder. 

Pinguecula 

This is a small, raised conjunctival nodule at the temporal 
or nasal limbus. In adults such lesions are extremely com- 
mon and have little significance, unless they become 
inflamed (pingueculitis). A pfery^wm resembles a pinguecula 
but has crossed the limbus to encroach upon the corneal 
surface. Removal is justified when symptoms of irritation 
f _ > or blurring develop, but recurrence is a common problem. 

3. Blepharitis 

9J This refers to inflammation of the eyelids. The most 
common form occurs in association with acne rosacea or 
seborrheic dermatitis. The eyelid margins are usually col- 
onized heavily by staphylococci. Upon close inspection, 
they appear greasy, ulcerated, and crusted with scaling 
debris that clings to the lashes. Treatment consists of warm 
compresses, strict eyelid hygiene, and topical antibiotics 
such as erythromycin. An external hordeolum (sty) is caused 
by staphylococcal infection of the superficial accessory 
glands of Zeis or Moll located in the eyelid margins. An 
internal hordeolum occurs after suppurative infection of 
the oil-secreting meibomian glands within the tarsal plate 
of the eyelid. Systemic antibiotics, usually tetracyclines, are 
sometimes necessary for treatment of meibomian gland 
inflammation (meibomitis) or chronic, severe blepharitis. 
A chalazion is a painless, granulomatous inflammation of a 
meibomian gland that produces a pealike nodule within 
the eyelid. It can be incised and drained, or injected with 
glucocorticoids. Basal cell, squamous cell, or meibomian 
gland carcinoma should be suspected for any nonhealing, 
ulcerative lesion of the eyelids. 

Dacrocystitis 

An inflammation of the lacrimal drainage system, this can 
produce epiphora (tearing) and ocular injection. Gentle 
pressure over the lacrimal sac evokes pain and reflux of 
mucus or pus from the tear puncta. Dacrocystitis usually 
occurs after obstruction of the lacrimal system. It is treated 
with topical and systemic antibiotics, followed by probing 
or surgery to reestablish patency. Entropion (inversion of 
the eyelid) or ectropion (sagging or eversion of the eyelid) 
can also lead to epiphora and ocular irritation. 

Conjunctivitis 

This is the most common cause of a red, irritated eye. 
Pain is minimal, and the visual acuity is reduced only 



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slightly. The most common viral etiology is adenovirus 
infection. It causes a watery discharge, mild foreign- 
body sensation, and photophobia. Bacterial infection 
tends to produce a more mucopurulent exudate. Mild 
cases of infectious conjunctivitis are usually treated empir- 
ically with broad-spectrum topical ocular antibiotics, such 
as sulfacetamide 10%, polymixin-bacitracin-neomycin, 
or trimethoprim-polymixin combination. Smears and 
cultures are usually reserved for severe, resistant, or recur- 
rent cases of conjunctivitis. To prevent contagion, patients 
should be admonished to wash their hands frequently, 
not to touch their eyes, and to avoid direct contact with 
others. 



Allergic Conjunctivitis 

This condition is extremely common and often mistaken 
for infectious conjunctivitis. Itching, redness, and epiphora 
are typical. The palpebral conjunctiva may become 
hypertropic with giant excrescences called cobblestone 
papillae. Irritation from contact lenses or any chronic for- 
eign body can also induce formation of cobblestone 
papillae. Atopic conjunctivitis occurs in subjects with atopic 
dermatitis or asthma. Symptoms caused by allergic con- 
junctivitis can be alleviated with cold compresses, topical 
vasoconstrictors, antihistamines, and mast cell stabilizers 
such as cromolyn sodium. Topical glucocorticoid solu- 
tions provide dramatic relief of immune -mediated forms 
of conjunctivitis, but their long-term use is ill-advised 
because of the complications of glaucoma, cataract, and 
secondary infection. Topical nonsteroidal anti-inflamma- 
tory agents (NSAIDs) such as ketorolac tromethamine 
are a better alternative. 



Keratoconjunctivitis Sicca 

Also known as dry eye, it produces a burning, foreign- 
body sensation, injection, and photophobia. In mild 
cases the eye appears surprisingly normal, but tear pro- 
duction measured by wetting of a filter paper (Schirmer 
strip) is deficient. A variety of systemic drugs, including 
antihistaminic, anticholinergic, and psychotropic med- 
ications, result in dry eye by reducing lacrimal secretion. 
Disorders that involve the lacrimal gland directly, such as 
sarcoidosis or Sjogren's syndrome, also cause dry eye. 
Patients may develop dry eye after radiation therapy if 
the treatment field includes the orbits. Problems with 
ocular drying are also common after lesions affecting 
cranial nerves V or VII. Corneal anesthesia is particularly 
dangerous, because the absence of a normal blink reflex 
exposes the cornea to injury without pain to warn the 
patient. Dry eye is managed by frequent and liberal 
application of artificial tears and ocular lubricants. In 
severe cases the tear puncta can be plugged or cauterized 
to reduce lacrimal outflow. 



Keratitis 

This is a threat to vision because of the risk of corneal 
clouding, scarring, and perforation. Worldwide, the two 
leading causes of blindness from keratitis are trachoma 
from chlamydial infection and vitamin A deficiency 
related to malnutrition. In the United States, contact lenses 
play a major role in corneal infection and ulceration. They 
should not be worn by anyone with an active eye infec- 
tion. In evaluating the cornea, it is important to differenti- 
ate between a superficial infection (keratoconjunctivitis) and 
a deeper, more serious ulcerative process. The latter is 
accompanied by greater visual loss, pain, photophobia, 
redness, and discharge. Slit-lamp examination shows dis- 
ruption of the corneal epithelium, a cloudy infiltrate or 
abscess in the stroma, and an inflammatory cellular reac- 
tion in the anterior chamber. In severe cases, pus settles at 
the bottom of the anterior chamber, giving rise to a 
hypopyon. Immediate empirical antibiotic therapy should 
be initiated after corneal scrapings are obtained for Gram's 
stain, Giemsa stain, and cultures. Fortified topical antibi- 
otics are most effective, supplemented with subconjuncti- 
val antibiotics as required. A fungal etiology should always 
be considered in the patient with keratitis. Fungal infec- 
tion is common in warm humid climates, especially after 
penetration of the cornea by plant or vegetable material. 

Herpes Simplex 

The herpes viruses are a major cause of blindness from 
keratitis. Most adults in the United States have serum 
antibodies to herpes simplex, indicating prior viral infec- 
tion. Primary ocular infection is generally caused by her- 
pes simplex type 1, rather than type 2. It manifests as a 
unilateral follicular blepharoconjunctivitis, easily con- 
fused with adenoviral conjunctivitis unless telltale vesicles 
appear on the periocular skin or conjunctiva. A dendritic 
pattern of corneal epithelial ulceration revealed by fluo- 
rescein staining is pathognomonic for herpes infection 
but is seen in only a minority of primary infections. 
Recurrent ocular infection arises from reactivation of the 
latent herpes virus. Viral eruption in the corneal epithe- 
lium may result in the characteristic herpes dendrite. 
Involvement of the corneal stroma produces edema, vas- 
cularization, and iridocyclitis. Herpes keratitis is treated 
with topical antiviral agents, cycloplegics, and oral acy- 
clovir. Topical glucocorticoids are effective in mitigating 
corneal scarring but must be used with extreme caution 
because of the danger of corneal melting and perfora- 
tion. Topical glucocorticoids also carry the risk of pro- 
longing infection and inducing glaucoma. 

Herpes Zoster 

Herpes zoster from reactivation of latent varicella (chick- 
enpox) virus causes a dermatomal pattern of painful 
vesicular dermatitis. Ocular symptoms can occur after 



zoster eruption in any branch of the trigeminal nerve "| 77 
but are particularly common when vesicles form on the 
nose, reflecting nasociliary (VI) nerve involvement 
(Hutchinson's sign). Herpes zoster ophthalmicus pro- 
duces corneal dendrites, which can be difficult to distin- 
guish from those seen in herpes simplex. Stromal keratitis, 
anterior uveitis, raised intraocular pressure, ocular motor 
nerve palsies, acute retinal necrosis, and postherpetic 
scarring and neuralgia are other common sequelae. 
Herpes zoster ophthalmicus is treated with antiviral 
agents and cycloplegics. In severe cases, glucocorticoids 
may be added to prevent permanent visual loss from 
corneal scarring. 

Episcleritis 



This is an inflammation of the episclera, a thin layer of 
connective tissue between the conjunctiva and sclera. 
Episcleritis resembles conjunctivitis but is a more local- 
ized process and discharge is absent. Most cases of epis- 
cleritis are idiopathic, but some occur in the setting of 
an autoimmune disease. Scleritis refers to a deeper, more 
severe inflammatory process, frequently associated with a 
connective tissue disease such as rheumatoid arthritis, 
lupus erythematosus, polyarteritis nodosa, Wegener's 
granulomatosis, or relapsing polychondritis. The inflam- 
mation and thickening of the sclera can be diffuse or 
nodular. In anterior forms of scleritis, the globe assumes 
a violet hue and the patient complains of severe ocular 
tenderness and pain. With posterior scleritis the pain and 
redness may be less marked, but there is often proptosis, 
choroidal effusion, reduced motility, and visual loss. 
Episcleritis and scleritis should be treated with NSAIDs. 
If these agents fail, topical or even systemic glucocorti- 
coid therapy may be necessary, especially if an underly- 
ing autoimmune process is active. 

Uveitis 

Involving the anterior structures of the eye, this is also 
called iritis or iridocyclitis. The diagnosis requires slit-lamp 
examination to identify inflammatory cells floating in the 
aqueous humor or deposited upon the corneal endothe- 
lium (keratic precipitates). Anterior uveitis develops in 
sarcoidosis, ankylosing spondylitis, juvenile rheumatoid 
arthritis, inflammatory bowel disease, psoriasis, Reiter's 
syndrome, and Behcet's disease. It is also associated with 
herpes infections, syphilis, Lyme disease, onchocerciasis, 
tuberculosis, and leprosy. Although anterior uveitis can 
occur in conjunction with many diseases, no cause is 
found to explain the majority of cases. For this reason, 
laboratory evaluation is usually reserved for patients with 
recurrent or severe anterior uveitis. Treatment is aimed at 
reducing inflammation and scarring by judicious use of 
topical glucocorticoids. Dilation of the pupil reduces 
pain and prevents the formation of synechiae. 






1 78 Posterior Uveitis 

This is diagnosed by observing inflammation of the 
vitreous, retina, or choroid on fundus examination. It is 
more likely than anterior uveitis to be associated with 
an identifiable systemic disease. Some patients have 
panuveitis, or inflammation of both the anterior and 
posterior segments of the eye. Posterior uveitis is a 
manifestation of autoimmune diseases such as sarcoido- 
sis, Behcet's disease, Vogt-Koyanagi-Harada syndrome, 
and inflammatory bowel disease (Fig. 17-4). It also 
accompanies diseases such as toxoplasmosis, onchocer- 
ciasis, cysticercosis, coccidioidomycosis, toxocariasis, and 
histoplasmosis; infections caused by organisms such as 
Candida, Pneumocystis carinii, Cryptococcus, Aspergillus, her- 
pes, and cytomegalovirus; and other diseases such as 
syphilis, Lyme disease, tuberculosis, cat-scratch disease, 
Whipple's disease, and brucellosis. In multiple sclerosis, 
chronic inflammatory changes can develop in the extreme 
periphery of the retina (pars planitis or intermediate 
uveitis) . 



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Acute Angle-Closure Glaucoma 

This is a rare and frequently misdiagnosed cause of a 
red, painful eye. Susceptible eyes have a shallow anterior 
chamber, either because the eye has a short axial length 
(hyperopia) or a lens enlarged by the gradual develop- 
ment of cataract. When the pupil becomes mid-dilated, 
the peripheral iris blocks aqueous outflow via the ante- 
rior chamber angle and the intraocular pressure rises 
abruptly, producing pain, injection, corneal edema, 
obscurations, and blurred vision. In some patients, ocular 
symptoms are overshadowed by nausea, vomiting, or 




FIGURE 17-4 

Retinal vasculitis, uveitis, and hemorrhage in a 32-year- 
old woman with Crohn's disease. Note that the veins are 
frosted with a white exudate. Visual acuity improved from 
20/400 to 20/20 following treatment with intravenous methyl- 
prednisolone. 



headache, prompting a fruitless workup for abdominal 
or neurologic disease. The diagnosis is made by measur- 
ing the intraocular pressure during an acute attack or by 
observing a narrow chamber angle by means of a spe- 
cially mirrored contact lens. Acute angle closure is 
treated with acetazolamide (PO or IV), topical beta 
blockers, prostaglandin analogues, OC 2 -adrenergic ago- 
nists, and pilocarpine to induce miosis. If these measures 
fail, a laser can be used to create a hole in the peripheral 
iris to relieve pupillary block. Many physicians are reluc- 
tant to dilate patients routinely for fundus examination 
because they fear precipitating an angle-closure glaucoma. 
The risk is actually remote and more than outweighed 
by the potential benefit to patients of discovering a 
hidden fundus lesion visible only through a fully dilated 
pupil. Moreover, a single attack of angle closure after 
pharmacologic dilation rarely causes any permanent dam- 
age to the eye and serves as an inadvertent provocative 
test to identify patients with narrow angles who would 
benefit from prophylactic laser iridectomy. 



Endophthalmitis 

This occurs from bacterial, viral, fungal, or parasitic 
infection of the internal structures of the eye. It is usu- 
ally acquired by hematogenous seeding from a remote 
site. Chronically ill, diabetic, or immunosuppressed 
patients, especially those with a history of indwelling IV 
catheters or positive blood cultures, are at greatest risk 
for endogenous endophthalmitis. Although most patients 
have ocular pain and injection, visual loss is sometimes 
the only symptom. Septic emboli, from a diseased heart 
valve or a dental abscess, that lodge in the retinal circula- 
tion can give rise to endophthalmitis. White-centered 
retinal hemorrhages (Roth's spots) are considered pathog- 
nomonic for subacute bacterial endocarditis, but they 
also appear in leukemia, diabetes, and many other condi- 
tions. Endophthalmitis also occurs as a complication of 
ocular surgery, occasionally months or even years after 
the operation. An occult penetrating foreign body or 
unrecognized trauma to the globe should be considered 
in any patient with unexplained intraocular infection or 
inflammation. 



TRANSIENT OR SUDDEN VISUAL LOSS 

Amaurosis Fugax 

This term refers to a transient ischemic attack of the 
retina (Chap. 21). Because neural tissue has a high rate of 
metabolism, interruption of blood flow to the retina for 
more than a few seconds results in transient monocular 
blindness, a term used interchangeably with amaurosis 
fugax. Patients describe a rapid fading of vision like a 
curtain descending, sometimes affecting only a portion 




FIGURE 17-5 

Hollenhorst plaque lodged at the bifurcation of a retinal 
arteriole proves that a patient is shedding emboli from either 
the carotid artery, great vessels, or heart. 



of the visual field. Amaurosis fugax usually occurs from 
an embolus that becomes stuck within a retinal arteriole 
(Fig. 17-5). If the embolus breaks up or passes, flow is 
restored and vision returns quickly to normal without 
permanent damage. With prolonged interruption of 
blood flow, the inner retina suffers infarction. Ophthal- 
moscopy reveals zones of whitened, edematous retina 
following the distribution of branch retinal arterioles. 
Complete occlusion of the central retinal artery pro- 
duces arrest of blood flow and a milky retina with a 
cherry-red fovea (Fig. 17-6). Emboli are composed of 
either cholesterol (Hollenhorst plaque), calcium, or 
platelet-fibrin debris. The most common source is an 
atherosclerotic plaque in the carotid artery or aorta, 
although emboli can also arise from the heart, especially 



in patients with diseased valves, atrial fibrillation, or wall 
motion abnormalities. 

In rare instances, amaurosis fugax occurs from low 
central retinal artery perfusion pressure in a patient with 
a critical stenosis of the ipsilateral carotid artery and 
poor collateral flow via the circle of Willis. In this situa- 
tion, amaurosis fugax develops when there is a dip in 
systemic blood pressure or a slight worsening of the 
carotid stenosis. Sometimes there is contralateral motor 
or sensory loss, indicating concomitant hemispheric 
cerebral ischemia. 

Retinal arterial occlusion also occurs rarely in associa- 
tion with retinal migraine, lupus erythematosus, anticar- 
diolipin antibodies (Fig. 17-6), anticoagulant deficiency 
states (protein S, protein C, and antithrombin III defi- 
ciency), pregnancy, IV drug abuse, blood dyscrasias, dys- 
proteinemias, and temporal arteritis. 

Marked systemic hypertension causes sclerosis of retinal 
arterioles, splinter hemorrhages, focal infarcts of the nerve 
fiber layer (cotton-wool spots), and leakage of lipid and 
fluid (hard exudate) into the macula (Fig. 17-7). In 
hypertensive crisis, sudden visual loss can result from 
vasospasm of retinal arterioles and retinal ischemia. In 
addition, acute hypertension may produce visual loss from 
ischemic swelling of the optic disc. Patients with acute 
hypertensive retinopathy should be treated by lowering 
the blood pressure. However, the blood pressure should 
not be reduced precipitously, because there is a danger of 
optic disc infarction from sudden hypoperfusion. 

Impending branch or central retinal vein occlusion can 
produce prolonged visual obscurations that resemble those 
described by patients with amaurosis fugax. The veins 
appear engorged and phlebitic, with numerous retinal 
hemorrhages (Fig. 17-8). In some patients, venous blood 



179 







FIGURE 17-6 

Central retinal artery occlusion combined with ischemic 
optic neuropathy in a 19-year-old woman with an elevated 
titer of anticardiolipin antibodies. Note the orange dot (rather 
than cherry red) corresponding to the fovea and the spared 
patch of retina just temporal to the optic disc. 




FIGURE 17-7 

Hypertensive retinopathy with scattered flame (splinter) 
hemorrhages and cotton-wool spots (nerve fiber layer 
infarcts) in a patient with headache and a blood pressure of 
234/120. 



180 



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FIGURE 1 7-8 

Central retinal vein occlusion can produce massive retinal 
hemorrhage ("blood and thunder"), ischemia, and vision loss. 



flow recovers spontaneously, -while others evolve a frank 
obstruction with extensive retinal bleeding ("blood and 
thunder" appearance), infarction, and visual loss. Venous 
occlusion of the retina is often idiopathic, but hyperten- 
sion, diabetes, and glaucoma are prominent risk factors. 
Polycythemia, thrombocythemia, or other factors leading 
to an underlying hypercoagulable state should be cor- 
rected; aspirin treatment may be beneficial. 

Anterior Ischemic Optic Neuropathy (AION) 

This is caused by insufficient blood flow through the pos- 
terior ciliary arteries supplying the optic disc. It produces 
painless, monocular visual loss that is usually sudden, 
although some patients have progressive worsening. The 
optic disc appears swollen and surrounded by nerve fiber 
layer splinter hemorrhages (Fig. 17-9). AION is divided 




FIGURE 17-9 

Anterior ischemic optic neuropathy from temporal arteri- 
tis in a 78-year-old woman with pallid disc swelling, hemor- 
rhage, visual loss, myalgia, and an erythrocyte sedimentation 
rate of 86 mm/h. 



into two forms: arteritic and nonarteritic. The nonar- 
teritic form of AION is most common. No specific cause 
can be identified, although diabetes and hypertension are 
frequent risk factors. No treatment is available. About 5% 
of patients, especially those older than 60 years, develop 
the arteritic form of AION in conjunction with giant cell 
(temporal) arteritis. It is urgent to recognize arteritic 
AION so that high doses of glucocorticoids can be insti- 
tuted immediately to prevent blindness in the second eye. 
Symptoms of polymyalgia rheumatica may be present; the 
sedimentation rate and C-reactive protein level are usually 
elevated. In a patient with visual loss from suspected 
arteritic AION, temporal artery biopsy is mandatory to 
confirm the diagnosis. Glucocorticoids should be started 
immediately, without waiting for the biopsy to be com- 
pleted. The diagnosis of arteritic AION is difficult to 
sustain in the face of a negative temporal artery biopsy, 
but such cases do occur rarely. 

Posterior Ischemic Optic Neuropathy 

This is an infrequent cause of acute visual loss, induced 
by the combination of severe anemia and hypotension. 
Cases have been reported after major blood loss during 
surgery, exsanguinating trauma, gastrointestinal bleeding, 
and renal dialysis. The fundus usually appears normal, 
although optic disc swelling develops if the process 
extends far enough anteriorly. Vision can be salvaged in 
some patients by prompt blood transfusion and reversal 
of hypotension. 

Optic Neuritis 

This is a common inflammatory disease of the optic 
nerve. In the Optic Neuritis Treatment Trial (ONTT), 
the mean age of patients was 32 years, 77% were women, 
92% had ocular pain (especially with eye movements), 
and 35% had optic disc swelling. In most patients, the 
demyelinating event was retrobulbar and the ocular fun- 
dus appeared normal on initial examination (Fig. 17-10), 
although optic disc pallor slowly developed over subse- 
quent months. 

Virtually all patients experience a gradual recovery of 
vision after a single episode of optic neuritis, even with- 
out treatment. This rule is so reliable that failure of vision 
to improve after a first attack of optic neuritis casts doubt 
upon the original diagnosis. Treatment with high-dose 
IV methylprednisolone (250 mg every 6 h for 3 days) 
followed by oral prednisone (1 mg/kg per day for 1 1 days) 
makes no difference in final acuity (measured 6 months 
after the attack), but the recovery of visual function 
occurs more rapidly. 

For some patients, optic neuritis remains an isolated 
event. However, the ONTT showed that the 10-year 
cumulative probability of developing clinically definite 
multiple sclerosis following optic neuritis is 38%. In 




FIGURE 17-10 

Retrobulbar optic neuritis is characterized by a normal fun- 
dus examination initially, hence the rubric, "the doctor sees 
nothing, and the patient sees nothing." Optic atrophy devel- 
ops after severe or repeated attacks. 




181 



FIGURE 17-11 

Optic atrophy is not a specific diagnosis, but refers to the 
combination of optic disc pallor, arteriolar narrowing, and 
nerve fiber layer destruction produced by a host of eye dis- 
eases, especially optic neuropathies. 



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patients with two or more demyelinating plaques on 
brain magnetic resonance (MR) imaging, treatment with 
interferon beta- la can retard the development of more 
lesions. In summary, an MR scan is recommended in 
every patient with a first attack of optic neuritis. When 
visual loss is severe (worse than 20/100), treatment with 
intravenous followed by oral glucocorticoids hastens 
recovery. If multiple lesions are present on the MR scan, 
treatment with interferon beta-la should be considered. 

Leber's Hereditary Optic Neuropathy 

This disease usually affects young men, causing gradual, 
painless, severe, central visual loss in one eye, followed 
weeks or months later by the same process in the other 
eye. Acutely, the optic disc appears mildly plethoric -with 
surface capillary telangiectases, but no vascular leakage on 
fluorescein angiography. Eventually optic atrophy ensues. 
Leber's optic neuropathy is caused by a point mutation at 
codon 11778 in the mitochondrial gene encoding nicoti- 
namide adenine dinucleotide dehydrogenase (NADH) 
subunit 4. Additional mutations responsible for the disease 
have been identified, most in mitochondrial genes encod- 
ing proteins involved in electron transport. Mitochondrial 
mutations causing Leber's neuropathy are inherited from 
the mother by all her children, but usually only sons 
develop symptoms. There is no treatment. 

Toxic Optic Neuropathy 

This can result in acute visual loss with bilateral optic 
disc swelling and central or cecocentral scotomas. Such 
cases have been reported to result from exposure to 
ethambutol, methyl alcohol (moonshine), ethylene glycol 
(antifreeze), or carbon monoxide. In toxic optic neuropathy, 



visual loss can also develop gradually and produce optic 
atrophy (Fig. 17-11) without a phase of acute optic disc 
edema. Many agents have been implicated as a cause of 
toxic optic neuropathy, but the evidence supporting the 
association for many is weak. The following is a partial 
list of potential offending drugs or toxins: disulfiram, 
ethchlorvynol, chloramphenicol, amiodarone, monoclonal 
anti-CD3 antibody, ciprofloxacin, digitalis, streptomycin, 
lead, arsenic, thallium, D-penicillamine, isoniazid, eme- 
tine, and sulfonamides. Deficiency states, induced either 
by starvation, malabsorption, or alcoholism, can lead to 
insidious visual loss. Thiamine, vitamin B 12 , and folate 
levels should be checked in any patient with unex- 
plained, bilateral central scotomas and optic pallor. 



Papilledema 

This connotes bilateral optic disc swelling from raised 
intracranial pressure (Fig. 17-12). Headache is a frequent, 
but not invariable, accompaniment. All other forms of 
optic disc swelling, e.g., from optic neuritis or ischemic 
optic neuropathy, should be called "optic disc edema." 
This convention is arbitrary but serves to avoid confusion. 
Often it is difficult to differentiate papilledema from other 
forms of optic disc edema by fundus examination alone. 
Transient visual obscurations are a classic symptom of 
papilledema. They can occur in only one eye or simulta- 
neously in both eyes. They usually last seconds but can 
persist longer. Obscurations follow abrupt shifts in posture 
or happen spontaneously. When obscurations are pro- 
longed or spontaneous, the papilledema is more threaten- 
ing. Visual acuity is not affected by papilledema unless 
the papilledema is severe, long-standing, or accompanied 
by macular edema and hemorrhage. Visual field testing 



182 




FIGURE 17-12 

Papilledema means optic disc edema from raised intracra- 
nial pressure. This obese young woman with pseudotumor 
cerebri was misdiagnosed as a migraineur until fundus 
examination was performed, showing optic disc elevation, 
hemorrhages, and cotton-wool spots. 




FIGURE 17-13 

Optic disc drusen are calcified deposits of unknown etiol- 
ogy within the optic disc. They are sometimes confused with 
papilledema. 



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shows enlarged blind spots and peripheral constriction 
(Fig. 17-3F). With unremitting papilledema, peripheral 
visual field loss progresses in an insidious fashion while 
the optic nerve develops atrophy. In this setting, reduction 
of optic disc swelling is an ominous sign of a dying nerve 
rather than an encouraging indication of resolving 
papilledema. 

Evaluation of papilledema requires neuroimaging 
to exclude an intracranial lesion. MR angiography is 
appropriate in selected cases to search for a dural venous 
sinus occlusion or an arteriovenous shunt. If neuroradio- 
logic studies are negative, the subarachnoid opening 
pressure should be measured by lumbar puncture. An 
elevated pressure, with normal cerebrospinal fluid, points 
by exclusion to the diagnosis of pseudotumor cerebri (idio- 
pathic intracranial hypertension). The majority of patients 
are young, female, and obese. Treatment -with a carbonic 
anhydrase inhibitor such as acetazolamide lowers intracra- 
nial pressure by reducing the production of cerebrospinal 
fluid. Weight reduction is vital but often unsuccessful. If 
acetazolamide and weight loss fail, and visual field loss is 
progressive, a shunt should be performed without delay 
to prevent blindness. Occasionally, emergency surgery 
is required for sudden blindness caused by fulminant 
papilledema. 

Optic Disc Drusen 

These are refractile deposits within the substance of the 
optic nerve head (Fig. 17-13). They are unrelated to 
drusen of the retina, which occur in age-related macular 
degeneration. Optic disc drusen are most common in 
people of northern European descent. Their diagnosis is 
obvious when they are visible as glittering particles upon 



the surface of the optic disc. However, in many patients 
they are hidden beneath the surface, producing pseudo- 
papilledema. It is important to recognize optic disc drusen 
to avoid an unnecessary evaluation for papilledema. 
Ultrasound or CT scanning is sensitive for detection of 
buried optic disc drusen because they contain calcium. 
In most patients, optic disc drusen are an incidental, 
innocuous finding, but they can produce visual obscura- 
tions. On perimetry they give rise to enlarged blind spots 
and arcuate scotomas from damage to the optic disc. With 
increasing age, drusen tend to become more exposed on 
the disc surface as optic atrophy develops. Hemorrhage, 
choroidal neovascular membrane, and AION are more 
likely to occur in patients with optic disc drusen. No treat- 
ment is available. 

Vitreous Degeneration 

This occurs in all individuals with advancing age, lead- 
ing to visual symptoms. Opacities develop in the vitre- 
ous, casting annoying shadows upon the retina. As the 
eye moves, these distracting "floaters" move synchro- 
nously, with a slight lag caused by inertia of the vitreous 
gel. Vitreous traction upon the retina causes mechanical 
stimulation, resulting in perception of flashing lights. 
This photopsia is brief and confined to one eye, in con- 
trast to the bilateral, prolonged scintillations of cortical 
migraine. Contraction of the vitreous can result in sud- 
den separation from the retina, heralded by an alarming 
shower of floaters and photopsia. This process, known as 
vitreous detachment, is a frequent involutional event in the 
elderly. It is not harmful unless it damages the retina. A 
careful examination of the dilated fundus is important in 
any patient complaining of floaters or photopsia to 



search for peripheral tears or holes. If such a lesion is 
found, laser application can forestall a retinal detach- 
ment. Occasionally a tear ruptures a retinal blood vessel, 
causing vitreous hemorrhage and sudden loss of vision. 
On attempted ophthalmoscopy the fundus is hidden by 
a dark red haze of blood. Ultrasound is required to 
examine the interior of the eye for a retinal tear or 
detachment. If the hemorrhage does not resolve sponta- 
neously, the vitreous can be removed surgically. Vitreous 
hemorrhage also occurs from the fragile neovascular 
vessels that proliferate on the surface of the retina in 
diabetes, sickle cell anemia, and other ischemic ocular 
diseases. 



Retinal Detachment 

This produces symptoms of floaters, flashing lights, and a 
scotoma in the peripheral visual field corresponding to 
the detachment (Fig. 17-14). If the detachment 
includes the fovea, there is an afferent pupil defect and 
the visual acuity is reduced. In most eyes, retinal detach- 
ment starts with a hole, flap, or tear in the peripheral 
retina (rhegmatogenous retinal detachment). Patients 
with peripheral retinal thinning (lattice degeneration) 
are particularly vulnerable to this process. Once a break 
has developed in the retina, liquified vitreous is free to 
enter the subretinal space, separating the retina from the 
pigment epithelium. The combination of vitreous trac- 
tion upon the retinal surface and passage of fluid behind 
the retina leads inexorably to detachment. Patients with 
a history of myopia, trauma, or prior cataract extraction 
are at greatest risk for retinal detachment. The diagnosis 
is confirmed by ophthalmoscopic examination of the 
dilated eye. 




FIGURE 17-14 

Retinal detachment appears as an elevated sheet of retinal 
tissue with folds. In this patient the fovea was spared, so 
acuity was normal, but a superior detachment produced an 
inferior scotoma. 



Classic Migraine 

(See also Chap. 6) This usually occurs with a visual aura 
lasting about 20 min. In a typical attack, a small central 
disturbance in the field of vision marches toward the 
periphery, leaving a transient scotoma in its wake. The 
expanding border of migraine scotoma has a scintillating, 
dancing, or zig-zag edge, resembling the bastions of a 
fortified city, hence the term fortification spectra. Patients' 
descriptions of fortification spectra vary widely and can 
be confused with amaurosis fugax. Migraine patterns usu- 
ally last longer and are perceived in both eyes, whereas 
amaurosis fugax is briefer and occurs in only one eye. 
Migraine phenomena also remain visible in the dark or 
with the eyes closed. Generally they are confined to either 
the right or left visual hemifield, but sometimes both 
fields are involved simultaneously. Patients often have a 
long history of stereotypic attacks. After the visual symp- 
toms recede, headache develops in most patients. 

Transient Ischemic Attacks 

Vertebrobasilar insufficiency may result in acute 
homonymous visual symptoms. Many patients mistak- 
enly describe symptoms in their left or right eye, when 
in fact they are occurring in the left or right hemifield 
of both eyes. Interruption of blood supply to the visual 
cortex causes a sudden fogging or graying of vision, 
occasionally with flashing lights or other positive phe- 
nomena that mimic migraine. Cortical ischemic attacks 
are briefer in duration than migraine, occur in older 
patients, and are not followed by headache. There may be 
associated signs of brainstem ischemia, such as diplopia, 
vertigo, numbness, weakness, or dysarthria. 

Stroke 

This occurs when interruption of blood supply from the 
posterior cerebral artery to the visual cortex is pro- 
longed. The only finding on examination is a homony- 
mous visual field defect that stops abruptly at the vertical 
meridian. Occipital lobe stroke is usually due to throm- 
botic occlusion of the vertebrobasilar system, embolus, or 
dissection. Lobar hemorrhage, tumor, abscess, and arteri- 
ovenous malformation are other common causes of hemi- 
anopic cortical visual loss. 

Factitious (Functional, Nonorganic) Visual Loss 

This is claimed by hysterics or malingerers. The latter 
comprise the vast majority, seeking sympathy, special treat- 
ment, or financial gain by feigning loss of sight. The diag- 
nosis is suspected when the history is atypical, physical 
findings are lacking or contradictory, inconsistencies 
emerge on testing, and a secondary motive can be identi- 
fied. In our litigious society, the fraudulent pursuit of rec- 
ompense has spawned an epidemic of factitious visual loss. 



183 



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184 CHRONIC VISUAL LOSS 
Cataract 

This is a clouding of the lens sufficient to reduce vision. 
Most cataracts develop slowly as a result of aging, leading 
to gradual impairment of vision. The formation of cataract 
occurs more rapidly in patients with a history of ocular 
trauma, uveitis, or diabetes mellitus. Cataracts are acquired 
in a variety of genetic diseases, such as myotonic dystro- 
phy, neurofibromatosis type 2, and galactosemia. Radiation 
therapy and glucocorticoid treatment can induce cataract 
as a side effect. The cataracts associated with radiation or 
glucocorticoids have a typical posterior subcapsular loca- 
tion. Cataract can be detected by noting an impaired red 
reflex when viewing light reflected from the fundus with 
an ophthalmoscope or by examining the dilated eye using 
the slit lamp. 

The only treatment for cataract is surgical extraction 
of the opacified lens. Over a million cataract operations 
are performed each year in the United States. The oper- 
ation is generally done under local anesthesia on an out- 
patient basis. A plastic or silicone intraocular lens is 
placed within the empty lens capsule in the posterior 
chamber, substituting for the natural lens and leading to 
rapid recovery of sight. More than 95% of patients who 
undergo cataract extraction can expect an improvement 
in vision. In some patients, the lens capsule remaining in 
the eye after cataract extraction eventually turns cloudy, 
causing secondary loss of vision. A small opening is 
made in the lens capsule with a laser to restore clarity. 



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Glaucoma 

This is a slowly progressive, insidious optic neuropathy, 
usually associated with chronic elevation of intraocular 
pressure. In Americans of African descent it is the leading 
cause of blindness. The mechanism whereby raised 
intraocular pressure injures the optic nerve is not under- 
stood. Axons entering the inferotemporal and superotem- 
poral aspects of the optic disc are damaged first, producing 
typical nerve fiber bundle or arcuate scotomas on peri- 
metric testing. As fibers are destroyed, the neural rim of 
the optic disc shrinks and the physiologic cup within the 
optic disc enlarges (Fig. 17-15). This process is referred to 
as pathologic "cupping." The cup-to-disc diameter is 
expressed as a ratio (e.g., 0.2/1). The cup-to-disc ratio 
ranges widely in normal individuals, making it difficult to 
diagnose glaucoma reliably simply by observing an unusu- 
ally large or deep optic cup. Careful documentation of ser- 
ial examinations is helpful. In the patient with physiologic 
cupping, the large cup remains stable, whereas in the 
patient with glaucoma it expands relendessly over the 
years. Detection of visual field loss by computerized 
perimetry also contributes to the diagnosis. Finally, most 
patients with glaucoma have raised intraocular pressure. 
However, many patients with typical glaucomatous cupping 




FIGURE 17-15 

Glaucoma results in "cupping" as the neural rim is 
destroyed and the central cup becomes enlarged and exca- 
vated. The cup-to-disc ratio is about 0.7/1 .0 in this patient. 



and visual field loss have intraocular pressures that appar- 
endy never exceed the normal limit of 20 mm Hg (so- 
called low-tension glaucoma) . 

In acute angle-closure glaucoma, the eye is red and 
painful due to abrupt, severe elevation of intraocular 
pressure. Such cases account for only a minority of glau- 
coma cases: most patients have open, anterior chamber 
angles. The cause of raised intraocular pressure in open 
angle glaucoma is unknown, but it is associated with 
gene mutations in the heritable forms. 

Glaucoma is usually painless (except in angle-closure 
glaucoma). Foveal acuity is spared until end-stage dis- 
ease is reached. For these reasons, severe and irreversible 
damage can occur before either the patient or physician 
recognizes the diagnosis. Screening of patients for glau- 
coma by noting the cup-to-disc ratio on ophthal- 
moscopy and by measuring intraocular pressure is vital. 
Glaucoma is treated with topical adrenergic agonists, 
cholinergic agonists, beta blockers, and prostaglandin ana- 
logues. Occasionally, systemic absorption of beta blocker 
from eye drops can be sufficient to cause side effects of 
bradycardia, hypotension, heart block, bronchospasm, or 
depression. Topical or oral carbonic anhydrase inhibitors 
are used to lower intraocular pressure by reducing 
aqueous production. Laser treatment of the trabecular 
meshwork in the anterior chamber angle improves 
aqueous outflow from the eye. If medical or laser treat- 
ments fail to halt optic nerve damage from glaucoma, a 
filter must be constructed surgically (trabeculectomy) or 
a valve placed to release aqueous from the eye in a con- 
trolled fashion. 



Macular Degeneration 

This is a major cause of gradual, painless, bilateral central 
visual loss in the elderly. The old term, "senile macular 



degeneration," misinterpreted by many patients as an 
unflattering reference, has been replaced with "age-related 
macular degeneration." It occurs in a nonexudative (dry) 
form and an exudative (wet) form. Inflammation may be 
important in both forms of macular degeneration; 
recent genetic data indicates that susceptibility is associ- 
ated with variants in the gene for complement factor H, 
an inhibitor of the alternative complement pathway. The 
nonexudative process begins with the accumulation of 
extracellular deposits, called drusen, underneath the reti- 
nal pigment epithelium. On ophthalmoscopy, they are 
pleomorphic but generally appear as small discrete 
yellow lesions clustered in the macula (Fig. 17-16). 
With time they become larger, more numerous, and 
confluent. The retinal pigment epithelium becomes focally 
detached and atrophic, causing visual loss by interfering 
with photoreceptor function. Treatment with vitamins 
C and E, beta carotene, and zinc may retard dry macular 
degeneration. 

Exudative macular degeneration, which develops in 
only a minority of patients, occurs when neovascular 
vessels from the choroid grow through defects in 
Bruch's membrane into the potential space beneath the 
retinal pigment epithelium. Leakage from these vessels 
produces elevation of the retina and pigment epithe- 
lium, with distortion (metamorphopsia) and blurring of 
vision. Although onset of these symptoms is usually 
gradual, bleeding from subretinal choroidal neovascular 
membranes sometimes causes acute visual loss. The neo- 
vascular membranes can be difficult to see on fundus 
examination because they are beneath the retina. Fluo- 
rescein or indocyanine green angiography is extremely 
useful for their detection. Neovascular membranes are 
treated with either photodynamic therapy or intraocular 
injection of vascular endothelial growth factor antago- 
nists. Surgical attempts to remove subretinal membranes 







FIGURE 17-16 

Age-related macular degeneration begins with the accu- 
mulation of drusen within the macula. They appear as scat- 
tered yellow subretinal deposits. 



in age-related macular degeneration have not improved 135 
vision in most patients. However, outcomes have been 
more encouraging for patients with choroidal neovascu- 
lar membranes from ocular histoplasmosis syndrome. 

Major or repeated hemorrhage under the retina from 
neovascular membranes results in fibrosis, development 
of a round (disciform) macular scar, and permanent loss 
of central vision. 

Central Serous Chorioretinopathy 

This primarily affects men between 20 and 50 years of 
age. Leakage of serous fluid from the choroid causes small, 
localized detachment of the retinal pigment epithelium 
and the neurosensory retina. These detachments produce 
acute or chronic symptoms of metamorphopsia and 
blurred vision when the macula is involved. They are dif- 
ficult to visualize with a direct ophthalmoscope because 
the detached retina is transparent and only slightly ele- 
vated. Diagnosis of central serous chorioretinopathy is 
made easily by fluorescein angiography, which shows dye 
streaming into the subretinal space. The cause of central 
serous chorioretinopathy is unknown. Symptoms may 
resolve spontaneously if the retina reattaches, but recur- 
rent detachment is common. Laser photocoagulation has 
benefited some patients with this condition. 

Diabetic Retinopathy 

A rare disease until 1921, when the discovery of insulin 
resulted in a dramatic improvement in life expectancy 
for patients with diabetes mellitus, it is now a leading 
cause of blindness in the United States. The retinopathy 
of diabetes takes years to develop but eventually appears 
in nearly all cases. Regular surveillance of the dilated 
fundus is crucial for any patient with diabetes. In 
advanced diabetic retinopathy, the proliferation of neovas- 
cular vessels leads to blindness from vitreous hemorrhage, 
retinal detachment, and glaucoma. These complications 
can be avoided in most patients by administration of 
panretinal laser photocoagulation at the appropriate point 
in the evolution of the disease. 

Retinitis Pigmentosa 

This is a general term for a disparate group of rod and 
cone dystrophies characterized by progressive night blind- 
ness, visual field constriction with a ring scotoma, loss of 
acuity, and an abnormal electro retinogram (ERG). It 
occurs sporadically or in an autosomal recessive, domi- 
nant, or X-linked pattern. Irregular black deposits of 
clumped pigment in the peripheral retina, called bone 
spicules because of their vague resemblance to the spicules 
of cancellous bone, give the disease its name (Fig. 17-17). 
The name is actually a misnomer because retinitis pig- 
mentosa is not an inflammatory process. Most cases are 



186 




FIGURE 17-17 

Retinitis pigmentosa with black clumps of pigment in the 
retinal periphery known as "bone spicules." There is also 
atrophy of the retinal pigment epithelium, making the vascu- 
lature of the choroid easily visible. 




FIGURE 17-18 

Melanoma of the choroid, appearing as an elevated dark 
mass in the inferior temporal fundus, just encroaching upon 
the fovea. 



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due to a mutation in the gene for rhodopsin, the rod 
photopigment, or in the gene for peripherin, a glycopro- 
tein located in photoreceptor outer segments. Vitamin A 
(15,000 IU/day) slightly retards the deterioration of the 
ERG in patients with retinitis pigmentosa but has no 
beneficial effect on visual acuity or fields. Some forms of 
retinitis pigmentosa occur in association with rare, hered- 
itary systemic diseases (olivopontocerebellar degenera- 
tion, Bassen-Kornzweig disease, Kearns-Sayre syndrome, 
Refsum's disease). Chronic treatment with chloroquine, 
hydroxychloroquine, and phenothiazines (especially thior- 
idazine) can produce visual loss from a toxic retinopathy 
that resembles retinitis pigmentosa. 

Epiretinal Membrane 

This is a fibrocellular tissue that grows across the inner 
surface of the retina, causing metamorphopsia and 
reduced visual acuity from distortion of the macula. A 
crinkled, cellophane-like membrane is visible on the 
retinal examination. Epiretinal membrane is most com- 
mon in patients older than 50 years and is usually unilat- 
eral. Most cases are idiopathic, but some occur as a result 
of hypertensive retinopathy, diabetes, retinal detachment, 
or trauma. When visual acuity is reduced to the level of 
about 6/24 (20/80), vitrectomy and surgical peeling of 
the membrane to relieve macular puckering are recom- 
mended. Contraction of an epiretinal membrane some- 
times gives rise to a macular hole. Most macular holes, 
however, are caused by local vitreous traction within the 
fovea. Vitrectomy can improve acuity in selected cases. 

Melanoma and Other Tumors 

Melanoma is the most common primary tumor of the eye 
(Fig. 17-18). It causes photopsia, an enlarging scotoma, 



and loss of vision. A small melanoma is often difficult to 
differentiate from a benign choroidal nevus. Serial exam- 
inations are required to document a malignant pattern of 
growth. Treatment of melanoma is controversial. Options 
include enucleation, local resection, and irradiation. 
Metastatic tumors to the eye outnumber primary tumors. 
Breast and lung carcinoma have a special propensity to 
spread to the choroid or iris. Leukemia and lymphoma 
also commonly invade ocular tissues. Sometimes their 
only sign on eye examination is cellular debris in the vit- 
reous, which can masquerade as a chronic posterior 
uveitis. Retrobulbar tumor of the optic nerve (meningioma, 
glioma) or chiasmal tumor (pituitary adenoma, menin- 
gioma) produces gradual visual loss with few objective 
findings, except for optic disc pallor. Rarely, sudden 
expansion of a pituitary adenoma from infarction and 
bleeding (pituitary apoplexy) causes acute retrobulbar visual 
loss, with headache, nausea, and ocular motor nerve 
palsies. In any patient with visual field loss or optic atro- 
phy, CT or MR scanning should be considered if the 
cause remains unknown after careful review of the his- 
tory and thorough examination of the eye. 



PROPTOSIS 

When the globes appear asymmetric, the clinician must 
first decide which eye is abnormal. Is one eye recessed 
within the orbit (enophthalmos) or is the other eye protu- 
berant (exophthalmos, or proptosis)? A small globe or a 
Horner's syndrome can give the appearance of enoph- 
thalmos. True enophthalmos occurs commonly after 
trauma, from atrophy of retrobulbar fat, or fracture of 
the orbital floor. The position of the eyes within the 
orbits is measured using a Hertel exophthalmometer, a 
hand-held instrument that records the position of the 



anterior corneal surface relative to the lateral orbital rim. 
If this instrument is not available, relative eye position 
can be judged by bending the patient's head forward and 
looking down upon the orbits. A proptosis of only 2 mm 
in one eye is detectable from this perspective. The devel- 
opment of proptosis implies a space-occupying lesion in 
the orbit, and usually warrants CT or MR imaging. 

Graves' Ophthalmopathy 

This is the leading cause of proptosis in adults. The prop- 
tosis is often asymmetric and can even appear to be uni- 
lateral. Orbital inflammation and engorgement of the 
extraocular muscles, particularly the medial rectus and the 
inferior rectus, account for the protrusion of the globe. 
Corneal exposure, lid retraction, conjunctival injection, 
restriction of gaze, diplopia, and visual loss from optic 
nerve compression are cardinal symptoms. Graves' oph- 
thalmopathy is treated with oral prednisone (60 mg/d) for 
1 month, followed by a taper over several months, topical 
lubricants, eyelid surgery, eye muscle surgery, or orbital 
decompression. Radiation therapy is not effective. 

Orbital Pseudotumor 

This is an idiopathic, inflammatory orbital syndrome, fre- 
quently confused with Graves' ophthalmopathy. Symptoms 
are pain, limited eye movements, proptosis, and congestion. 
Evaluation for sarcoidosis, Wegener's granulomatosis, and 
other types of orbital vasculitis or collagen-vascular disease 
is negative. Imaging often shows swollen eye muscles 
(orbital myositis) with enlarged tendons. By contrast, in 
Graves' ophthalmopathy the tendons of the eye muscles are 
usually spared. The Tolosa-Hunt syndrome may be regarded 
as an extension of orbital pseudotumor through the supe- 
rior orbital fissure into the cavernous sinus. The diagnosis 
of orbital pseudotumor is difficult. Biopsy of the orbit fre- 
quently yields nonspecific evidence of fat infiltration by 
lymphocytes, plasma cells, and eosinophils. A dramatic 
response to a therapeutic trial of systemic glucocorticoids 
indirecdy provides the best confirmation of the diagnosis. 

Orbital Cellulitis 

This causes pain, lid erythema, proptosis, conjunctival 
chemosis, restricted motility, decreased acuity, afferent 
pupillary defect, fever, and leukocytosis. It often arises 
from the paranasal sinuses, especially by contiguous 
spread of infection from the ethmoid sinus through the 
lamina papyracea of the medial orbit. A history of recent 
upper respiratory tract infection, chronic sinusitis, thick 
mucous secretions, or dental disease is significant in any 
patient with suspected orbital cellulitis. Blood cultures 
should be obtained, but they are usually negative. Most 
patients respond to empirical therapy with broad- 
spectrum IV antibiotics. Occasionally, orbital cellulitis 
follows an overwhelming course, with massive proptosis, 



blindness, septic cavernous sinus thrombosis, and menin- 187 
gitis. To avert this disaster, orbital cellulitis should be 
managed aggressively in the early stages, with immediate 
imaging of the orbits and antibiotic therapy that 
includes coverage of methicillin-resistant Staphylococcus 
aureus. Prompt surgical drainage of an orbital abscess or 
paranasal sinusitis is indicated if optic nerve function 
deteriorates despite antibiotics. 

Tumors 



Tumors of the orbit cause painless, progressive proptosis. 
The most common primary tumors are hemangioma, 
lymphangioma, neurofibroma, dermoid cyst, adenoid 
cystic carcinoma, optic nerve glioma, optic nerve menin- 
gioma, and benign mixed tumor of the lacrimal gland. 
Metastatic tumor to the orbit occurs frequently in breast 
carcinoma, lung carcinoma, and lymphoma. Diagnosis 
by fine-needle aspiration followed by urgent radiation 
therapy can sometimes preserve vision. 



Carotid Cavernous Fistulas 

With anterior drainage through the orbit these produce 
proptosis, diplopia, glaucoma, and corkscrew, arterialized 
conjunctival vessels. Direct fistulas usually result from 
trauma. They are easily diagnosed because of the promi- 
nent signs produced by high-flow, high-pressure shunting. 
Indirect fistulas, or dural arteriovenous malformations, are 
more likely to occur spontaneously, especially in older 
women. The signs are more subtle and the diagnosis is 
frequently missed. The combination of slight proptosis, 
diplopia, enlarged muscles, and an injected eye is often 
mistaken for thyroid ophthalmopathy. A bruit heard upon 
auscultation of the head, or reported by the patient, is a 
valuable diagnostic clue. Imaging shows an enlarged supe- 
rior ophthalmic vein in the orbits. Carotid cavernous 
shunts can be eliminated by intravascular embolization. 

PTOSIS 
Blepharoptosis 

This is an abnormal drooping of the eyelid. Unilateral or 
bilateral ptosis can be congenital, from dysgenesis of the 
levator palpebrae superioris, or from abnormal insertion 
of its aponeurosis into the eyelid. Acquired ptosis can 
develop so gradually that the patient is unaware of the 
problem. Inspection of old photographs is helpful in 
dating the onset. A history of prior trauma, eye surgery, 
contact lens use, diplopia, systemic symptoms (e.g., dys- 
phagia or peripheral muscle weakness), or a family his- 
tory of ptosis should be sought. Fluctuating ptosis that 
worsens late in the day is typical of myasthenia gravis. 
Examination should focus upon evidence for proptosis, 
eyelid masses or deformities, inflammation, pupil 
inequality, or limitation of motility. The width of the 






188 palpebral fissures is measured in primary gaze to quanti- 
tate the degree of ptosis. The ptosis will be underesti- 
mated if the patient compensates by lifting the brow 
with the frontalis muscle. 



Mechanical Ptosis 

This occurs in many elderly patients from stretching and 
redundancy of eyelid skin and subcutaneous fat (derma- 
tochalasis). The extra weight of these sagging tissues 
causes the lid to droop. Enlargement or deformation of 
the eyelid from infection, tumor, trauma, or inflamma- 
tion also results in ptosis on a purely mechanical basis. 

Aponeurotic Ptosis 

This is an acquired dehiscence or stretching of the 
aponeurotic tendon, which connects the levator muscle 
to the tarsal plate of the eyelid. It occurs commonly in 
older patients, presumably from loss of connective tissue 
elasticity. Aponeurotic ptosis is also a frequent sequela of 
eyelid swelling from infection or blunt trauma to the 
orbit, cataract surgery, or hard contact lens usage. 



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The causes of myogenic ptosis include myasthenia gravis 
(Chap. 42) and a number of rare myopathies that mani- 
fest with ptosis. The term chronic progressive external oph- 
thalmoplegia refers to a spectrum of systemic diseases 
caused by mutations of mitochondrial DNA. As the 
name implies, the most prominent findings are symmet- 
ric, slowly progressive ptosis and limitation of eye move- 
ments. In general, diplopia is a late symptom because all 
eye movements are reduced equally. In the Keams-Sayre 
variant, retinal pigmentary changes and abnormalities of 
cardiac conduction develop. Peripheral muscle biopsy 
shows characteristic "ragged-red fibers." Oculopharyngeal 
dystrophy is a distinct autosomal dominant disease with 
onset in middle age, characterized by ptosis, limited eye 
movements, and trouble swallowing. Myotonic dystrophy, 
another autosomal dominant disorder, causes ptosis, 
ophthalmoparesis, cataract, and pigmentary retinopathy. 
Patients have muscle wasting, myotonia, frontal balding, 
and cardiac abnormalities. 

Neurogenic Ptosis 

This results from a lesion affecting the innervation to 
either of the two muscles that open the eyelid: Miiller's 
muscle or the levator palpebrae superioris. Examination 
of the pupil helps to distinguish between these two pos- 
sibilities. In Horner's syndrome, the eye with ptosis has a 
smaller pupil and the eye movements are full. In an ocu- 
lomotor nerve palsy, the eye with the ptosis has a larger, 
or a normal, pupil. If the pupil is normal but there is 



limitation of adduction, elevation, and depression, a 
pupil-sparing oculomotor nerve palsy is likely (see next 
section). Rarely, a lesion affecting the small, central sub- 
nucleus of the oculomotor complex will cause bilateral 
ptosis with normal eye movements and pupils. 

DOUBLE VISION (DIPLOPIA) 

The first point to clarify is whether diplopia persists in 
either eye after covering the opposite eye. If it does, the 
diagnosis is monocular diplopia. The cause is usually 
intrinsic to the eye and therefore has no dire implica- 
tions for the patient. Corneal aberrations (e.g., kerato- 
conus, pterygium), uncorrected refractive error, cataract, 
or foveal traction may give rise to monocular diplopia. 
Occasionally it is a symptom of malingering or psychi- 
atric disease. Diplopia alleviated by covering one eye is 
binocular diplopia and is caused by disruption of ocular 
alignment. Inquiry should be made into the nature of 
the double vision (purely side-by-side versus partial ver- 
tical displacement of images), mode of onset, duration, 
intermittency, diurnal variation, and associated neuro- 
logic or systemic symptoms. If the patient has diplopia 
while being examined, motility testing should reveal a 
deficiency corresponding to the patient's symptoms. 
However, subtle limitation of ocular excursions is often 
difficult to detect. For example, a patient with a slight 
left abducens nerve paresis may appear to have full eye 
movements, despite a complaint of horizontal diplopia 
upon looking to the left. In this situation, the cover test 
provides a more sensitive method for demonstrating the 
ocular misalignment. It should be conducted in primary 
gaze, and then with the head turned and tilted in each 
direction. In the above example, a cover test with the 
head turned to the right will maximize the fixation shift 
evoked by the cover test. 

Occasionally, a cover test performed in an asympto- 
matic patient during a routine examination will reveal 
an ocular deviation. If the eye movements are full and 
the ocular misalignment is equal in all directions of gaze 
(concomitant deviation), the diagnosis is strabismus. In 
this condition, which affects about 1% of the popula- 
tion, fusion is disrupted in infancy or early childhood. 
To avoid diplopia, vision is suppressed from the nonfix- 
ating eye. In some children, this leads to impaired vision 
(amblyopia, or "lazy" eye) in the deviated eye. 

Binocular diplopia occurs from a wide range of 
processes: infectious, neoplastic, metabolic, degenerative, 
inflammatory, and vascular. One must decide if the diplopia 
is neurogenic in origin or due to restriction of globe rota- 
tion by local disease in the orbit. Orbital pseudotumor, 
myositis, infection, tumor, thyroid disease, and muscle 
entrapment (e.g., from a blowout fracture) cause restrictive 
diplopia. The diagnosis of restriction is usually made by rec- 
ognizing other associated signs and symptoms of local 
orbital disease in conjunction with imaging. 



Myasthenia Gravis 

(See Chap. 42) This is a major cause of diplopia. The 
diplopia is often intermittent, variable, and not confined 
to any single ocular motor nerve distribution. The pupils 
are always normal. Fluctuating ptosis may be present. 
Many patients have a purely ocular form of the disease, 
with no evidence of systemic muscular weakness. The 
diagnosis can be confirmed by an IV edrophonium 
injection or by an assay for antiacetylcholine receptor 
antibodies. Negative results from these tests do not 
exclude the diagnosis. Botulism from food or wound 
poisoning can mimic ocular myasthenia. 

After restrictive orbital disease and myasthenia gravis 
are excluded, a lesion of a cranial nerve supplying inner- 
vation to the extraocular muscles is the most likely cause 
of binocular diplopia. 



Oculomotor Nerve 

The third cranial nerve innervates the medial, inferior, 
and superior recti; inferior oblique; levator palpebrae 
superioris; and the iris sphincter. Total palsy of the ocu- 
lomotor nerve causes ptosis, a dilated pupil, and leaves 
the eye "down and out" because of the unopposed 
action of the lateral rectus and superior oblique. This 
combination of findings is obvious. More challenging is 
the diagnosis of early or partial oculomotor nerve palsy. 
In this setting, any combination of ptosis, pupil dilation, 
and weakness of the eye muscles supplied by the oculo- 
motor nerve may be encountered. Frequent serial exam- 
inations during the evolving phase of the palsy help 
ensure that the diagnosis is not missed. The advent of an 
oculomotor nerve palsy with a pupil involvement, espe- 
cially when accompanied by pain, suggests a compressive 
lesion, such as a tumor or circle of Willis aneurysm. 
Neuroimaging should be obtained, along with a CT or 
MR angiogram. Occasionally, a catheter arteriogram must 
be done to exclude an aneurysm. 

A lesion of the oculomotor nucleus in the rostral 
midbrain produces signs that differ from those caused by 
a lesion of the nerve itself. There is bilateral ptosis 
because the levator muscle is innervated by a single cen- 
tral subnucleus. There is also weakness of the contralateral 
superior rectus, because it is supplied by the oculomotor 
nucleus on the other side. Occasionally both superior 
recti are weak. Isolated nuclear oculomotor palsy is rare. 
Usually neurologic examination reveals additional signs to 
suggest brainstem damage from infarction, hemorrhage, 
tumor, or infection. 

Injury to structures surrounding fascicles of the ocu- 
lomotor nerve descending through the midbrain has 
given rise to a number of classic eponymic designations. 
In Nothnagel's syndrome, injury to the superior cerebellar 
peduncle causes ipsilateral oculomotor palsy and con- 
tralateral cerebellar ataxia. In Benedikt's syndrome, injury 



to the red nucleus results in ipsilateral oculomotor palsy 
and contralateral tremor, chorea, and athetosis. Claude's 
syndrome incorporates features of both the aforemen- 
tioned syndromes, by injury to both the red nucleus and 
the superior cerebellar peduncle. Finally, in Weber's syn- 
drome, injury to the cerebral peduncle causes ipsilateral 
oculomotor palsy with contralateral hemiparesis. 

In the subarachnoid space the oculomotor nerve is 
vulnerable to aneurysm, meningitis, tumor, infarction, 
and compression. In cerebral herniation the nerve 
becomes trapped between the edge of the tentorium 
and the uncus of the temporal lobe. Oculomotor palsy 
can also occur from midbrain torsion and hemorrhages 
during herniation. In the cavernous sinus, oculomotor 
palsy arises from carotid aneurysm, carotid cavernous fis- 
tula, cavernous sinus thrombosis, tumor (pituitary ade- 
noma, meningioma, metastasis), herpes zoster infection, 
and the Tolosa-Hunt syndrome. 

The etiology of an isolated, pupil-sparing oculomotor 
palsy often remains an enigma, even after neuroimaging 
and extensive laboratory testing. Most cases are thought 
to result from microvascular infarction of the nerve, 
somewhere along its course from the brainstem to the 
orbit. Usually the patient complains of pain. Diabetes, 
hypertension, and vascular disease are major risk factors. 
Spontaneous recovery over a period of months is the 
rule. If this fails to occur, or if new findings develop, the 
diagnosis of microvascular oculomotor nerve palsy 
should be reconsidered. Aberrant regeneration is com- 
mon when the oculomotor nerve is injured by trauma or 
compression (tumor, aneurysm). Miswiring of sprouting 
fibers to the levator muscle and the rectus muscles results 
in elevation of the eyelid upon downgaze or adduction. 
The pupil also constricts upon attempted adduction, ele- 
vation, or depression of the globe. Aberrant regeneration 
is not seen after oculomotor palsy from microvascular 
infarct and hence vitiates that diagnosis. 

Trochlear Nerve 

The fourth cranial nerve originates in the midbrain, just 
caudal to the oculomotor nerve complex. Fibers exit the 
brainstem dorsally and cross to innervate the contralat- 
eral superior oblique. The principal actions of this muscle 
are to depress and to intort the globe. A palsy therefore 
results in hypertropia and excyclotorsion. The cyclotor- 
sion is seldom noticed by patients. Instead, they complain 
of vertical diplopia, especially upon reading or looking 
down. The vertical diplopia is also exacerbated by tilting 
the head toward the side with the muscle palsy, and alle- 
viated by tilting it away. This "head tilt test" is a cardinal 
diagnostic feature. 

Isolated trochlear nerve palsy occurs from all the causes 
listed above for the oculomotor nerve, except aneurysm. 
The trochlear nerve is particularly apt to suffer injury 
after closed head trauma. The free edge of the tentorium 



189 






ST 
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190 i s thought to impinge upon the nerve during a concussive 
blow. Most isolated trochlear nerve palsies are idiopathic 
and hence diagnosed by exclusion as "microvascular." 
Spontaneous improvement occurs over a period of 
months in most patients. A base-down prism (conve- 
niently applied to the patient's glasses as a stick-on Fresnel 
lens) may serve as a temporary measure to alleviate 
diplopia. If the palsy does not resolve, the eyes can be 
realigned by weakening the inferior oblique muscle. 

Abducens Nerve 

The sixth cranial nerve innervates the lateral rectus mus- 
cle. A palsy produces horizontal diplopia, worse on gaze 
to the side of the lesion. A nuclear lesion has different 
consequences, because the abducens nucleus contains 
interneurons that project via the medial longitudinal fas- 
ciculus to the medial rectus subnucleus of the contralat- 
eral oculomotor complex. Therefore, an abducens nuclear 
lesion produces a complete lateral gaze palsy, from weak- 
ness of both the ipsilateral lateral rectus and the contralat- 
eral medial rectus. Foville's syndrome following dorsal 
pontine injury includes lateral gaze palsy, ipsilateral facial 
palsy, and contralateral hemiparesis incurred by damage to 
descending corticospinal fibers. Millard-Gubler syndrome 
from ventral pontine injury is similar, except for the eye 
findings. There is lateral rectus weakness only, instead of 
gaze palsy, because the abducens fascicle is injured rather 
than the nucleus. Infarct, tumor, hemorrhage, vascular 
malformation, and multiple sclerosis are the most com- 
mon etiologies of brainstem abducens palsy. 

After leaving the ventral pons, the abducens nerve 
runs forward along the clivus to pierce the dura at the 
petrous apex, where it enters the cavernous sinus. Along its 
subarachnoid course it is susceptible to meningitis, tumor 
(meningioma, chordoma, carcinomatous meningitis), sub- 
arachnoid hemorrhage, trauma, and compression by 
aneurysm or dolichoectatic vessels. At the petrous apex, 
mastoiditis can produce deafness, pain, and ipsilateral 
abducens palsy (Gradenigo's syndrome). In the cavernous 
sinus, the nerve can be affected by carotid aneurysm, 
carotid cavernous fistula, tumor (pituitary adenoma, 
meningioma, nasopharyngeal carcinoma), herpes infec- 
tion, and Tolosa-Hunt syndrome. 

Unilateral or bilateral abducens palsy is a classic sign 
of raised intracranial pressure. The diagnosis can be con- 
firmed if papilledema is observed on fundus examina- 
tion. The mechanism is still debated but is probably 
related to rostral-caudal displacement of the brainstem. 
The same phenomenon accounts for abducens palsy from 
low intracranial pressure (e.g., after lumbar puncture, 
spinal anesthesia, or spontaneous dural cerebrospinal fluid 
leak). 

Treatment of abducens palsy is aimed at prompt correc- 
tion of the underlying cause. However, the cause remains 
obscure in many instances, despite diligent evaluation. 



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As mentioned above for isolated trochlear or oculomo- 
tor palsy, most cases are assumed to represent microvas- 
cular infarcts because they often occur in the setting of 
diabetes or other vascular risk factors. Some cases may 
develop as a postinfectious mononeuritis (e.g., following 
a viral flu). Patching one eye or applying a temporary 
prism will provide relief of diplopia until the palsy 
resolves. If recovery is incomplete, eye muscle surgery can 
nearly always realign the eyes, at least in primary posi- 
tion. A patient with an abducens palsy that fails to 
improve should be reevaluated for an occult etiology 
(e.g., chordoma, carcinomatous meningitis, carotid cav- 
ernous fistula, myasthenia gravis) . 



Multiple Ocular Motor Nerve Palsies 

These should not be attributed to spontaneous 
microvascular events affecting more than one cranial 
nerve at a time. This remarkable coincidence does occur, 
especially in diabetic patients, but the diagnosis is made 
only in retrospect after exhausting all other diagnostic 
alternatives. Neuro imaging should focus on the cav- 
ernous sinus, superior orbital fissure, and orbital apex, 
where all three ocular motor nerves are in close proxim- 
ity. In the diabetic or compromised host, fungal infec- 
tion (Aspergillus, Mucorales, Cryptococcus) is a frequent 
cause of multiple nerve palsies. In the patient with sys- 
temic malignancy, carcinomatous meningitis is a likely 
diagnosis. Cytologic examination may be negative 
despite repeated sampling of the cerebrospinal fluid. The 
cancer-associated Lambert-Eaton myasthenic syndrome 
can also produce ophthalmoplegia. Giant cell (temporal) 
arteritis occasionally manifests as diplopia from ischemic 
palsies of extraocular muscles. Fisher syndrome, an ocu- 
lar variant of Guillain-Barre, produces ophthalmoplegia 
with areflexia and ataxia. Often the ataxia is mild, and 
the reflexes are normal. Antiganglioside antibodies 
(GQlb) can be detected in about 50% of cases. 



Supranuclear Disorders of Gaze 

These are often mistaken for multiple ocular motor 
nerve palsies. For example, Wernicke's encephalopathy 
can produce nystagmus and a partial deficit of horizon- 
tal and vertical gaze that mimics a combined abducens 
and oculomotor nerve palsy. The disorder occurs in mal- 
nourished or alcoholic patients and can be reversed by 
thiamine. Infarct, hemorrhage, tumor, multiple sclerosis, 
encephalitis, vasculitis, and Whipple's disease are other 
important causes of supranuclear gaze palsy. Disorders of 
vertical gaze, especially downwards saccades, are an early 
feature of progressive supranuclear palsy. Smooth pursuit 
is affected later in the course of the disease. Parkinson's 
disease, Huntington's chorea, and olivopontocerebellar 
degeneration can also affect vertical gaze. 



The frontal eye field of the cerebral cortex is involved 
in generation of saccades to the contralateral side. After 
hemispheric stroke, the eyes usually deviate towards the 
lesioned side because of the unopposed action of the 
frontal eye field in the normal hemisphere. With time, 
this deficit resolves. Seizures generally have the opposite 
effect: the eyes deviate conjugately away from the irrita- 
tive focus. Parietal lesions disrupt smooth pursuit of targets 
moving toward the side of the lesion. Bilateral parietal 
lesions produce Balint's syndrome, characterized by 
impaired eye-hand coordination (optic ataxia), difficulty 
initiating voluntary eye movements (ocular apraxia), and 
visuospatial disorientation (simultanagnosia) . 

Horizontal Gaze 

Descending cortical inputs mediating horizontal gaze 
ultimately converge at the level of the pons. Neurons in 
the paramedian pontine reticular formation are respon- 
sible for controlling conjugate gaze toward the same 
side. They project directly to the ipsilateral abducens 
nucleus. A lesion of either the paramedian pontine retic- 
ular formation or the abducens nucleus causes an ipsilat- 
eral conjugate gaze palsy. Lesions at either locus produce 
nearly identical clinical syndromes, with the following 
exception: vestibular stimulation (oculocephalic maneu- 
ver or caloric irrigation) will succeed in driving the eyes 
conjugately to the side in a patient with a lesion of the 
paramedian pontine reticular formation, but not in a 
patient with a lesion of the abducens nucleus. 

^H Internuclear Ophthalmoplegia 

This results from damage to the medial longitudinal fas- 
ciculus ascending from the abducens nucleus in the pons 
to the oculomotor nucleus in the midbrain (hence, 
"internuclear"). Damage to fibers carrying the conju- 
gate signal from abducens interneurons to the contralat- 
eral medial rectus motoneurons results in a failure of 
adduction on attempted lateral gaze. For example, a 
patient with a left internuclear ophthalmoplegia will 
have slowed or absent adducting movements of the left 
eye (Fig. 17-19). A patient with bilateral injury to the 
medial longitudinal fasciculus will have bilateral inter- 
nuclear ophthalmoplegia. Multiple sclerosis is the most 
common cause, although tumor, stroke, trauma, or any 
brainstem process may be responsible. One-and-a-half 
syndrome is due to a combined lesion of the medial lon- 
gitudinal fasciculus and the abducens nucleus on the 
same side. The patient's only horizontal eye movement is 
abduction of the eye on the other side. 

Vertical Gaze 

This is controlled at the level of the midbrain. The neu- 
ronal circuits affected in disorders of vertical gaze are 
not fully elucidated, but lesions of the rostral interstitial 




FIGURE 17-19 

Left internuclear ophthalmoplegia (INO). A. In primary posi- 
tion of gaze the eyes appear normal. B. Horizontal gaze to the 
left is intact. C. On attempted horizontal gaze to the right, the 
left eye fails to adduct. In mildly affected patients the eye may 
adduct partially, or more slowly than normal. Nystagmus is 
usually present in the abducted eye. D. T2-weighted axial MRI 
image through the pons showing a demyelinating plaque in 
the left medial longitudinal fasciculus (arrow). 



192 



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nucleus of the medial longitudinal fasciculus and the 
interstitial nucleus of Cajal cause supranuclear paresis of 
upgaze, downgaze, or all vertical eye movements. Distal 
basilar artery ischemia is the most common etiology. 
Skew deviation refers to a vertical misalignment of the 
eyes, usually constant in all positions of gaze. The finding 
has poor localizing value because skew deviation has 
been reported after lesions in widespread regions of the 
brainstem and cerebellum. 

^H Parinaud's Syndrome 

Also known as dorsal midbrain syndrome, this is a distinct 
supranuclear vertical gaze disorder from damage to the 
posterior commissure. It is a classic sign of hydrocephalus 
from aqueductal stenosis. Pineal region tumors, cysticer- 
cosis, and stroke also cause Parinaud's syndrome. Features 
include loss of upgaze (and sometimes downgaze), con- 
vergence-retraction nystagmus on attempted upgaze, 
downwards ocular deviation ("setting sun" sign), lid retrac- 
tion (Collier's sign), skew deviation, pseudoabducens 
palsy, and light-near dissociation of the pupils. 

Nystagmus 

This is a rhythmical oscillation of the eyes, occurring 
physiologically from vestibular and optokinetic stimulation 
or pathologically in a wide variety of diseases (Chap. 9) . 
Abnormalities of the eyes or optic nerves, present at birth 
or acquired in childhood, can produce a complex, 
searching nystagmus with irregular pendular (sinusoidal) 
and jerk features. This nystagmus is commonly referred 
to as congenital sensory nystagmus. It is a poor term, because 
even in children with congenital lesions, the nystagmus 
does not appear until several months of age. Congenital 
motor nystagmus, which looks similar to congenital sensory 
nystagmus, develops in the absence of any abnormality of 
the sensory visual system. Visual acuity is also reduced in 
congenital motor nystagmus, probably by the nystagmus 
itself, but seldom below a level of 20/200. 

^H Jerk Nystagmus 

This is characterized by a slow drift off the target, fol- 
lowed by a fast corrective saccade. By convention, the 
nystagmus is named after the quick phase. Jerk nystag- 
mus can be downbeat, upbeat, horizontal (left or right), 
and torsional. The pattern of nystagmus may vary with 
gaze position. Some patients will be oblivious to their 
nystagmus. Others will complain of blurred vision, or a 
subjective, to-and-fro movement of the environment 
(oscillopsia) corresponding to their nystagmus. Fine nys- 
tagmus may be difficult to see upon gross examination 
of the eyes. Observation of nystagmoid movements of 
the optic disc on ophthalmoscopy is a sensitive way to 
detect subtle nystagmus. 



^H Gaze-Evoked Nystagmus 

This is the most common form of jerk nystagmus. 
When the eyes are held eccentrically in the orbits, they 
have a natural tendency to drift back to primary posi- 
tion. The subject compensates by making a corrective 
saccade to maintain the deviated eye position. Many 
normal patients have mild gaze-evoked nystagmus. 
Exaggerated gaze-evoked nystagmus can be induced by 
drugs (sedatives, anticonvulsants, alcohol); muscle paresis; 
myasthenia gravis; demyelinating disease; and cerebello- 
pontine angle, brainstem, and cerebellar lesions. 

^H Vestibular Nystagmus 

Vestibular nystagmus results from dysfunction of the 
labyrinth (Meniere's disease), vestibular nerve, or 
vestibular nucleus in the brainstem. Peripheral vestibular 
nystagmus often occurs in discrete attacks, with symptoms 
of nausea and vertigo. There may be associated tinnitus 
and hearing loss. Sudden shifts in head position may 
provoke or exacerbate symptoms. 

^H Downbeat Nystagmus 

Downbeat nystagmus occurs from lesions near the cranio- 
cervical junction (Chiari malformation, basilar invagina- 
tion) . It has also been reported in brainstem or cerebellar 
stroke, lithium or anticonvulsant intoxication, alcoholism, 
and multiple sclerosis. Upbeat nystagmus is associated 
with damage to the pontine tegmentum, from stroke, 
demyelination, or tumor. 

Opsoclonus 

This rare, dramatic disorder of eye movements consists 
of bursts of consecutive saccades (saccadomania). When 
the saccades are confined to the horizontal plane, the 
term ocular flutter is preferred. It can occur from viral 
encephalitis, trauma, or a paraneoplastic effect of neu- 
roblastoma, breast carcinoma, and other malignancies. It 
has also been reported as a benign, transient phenomenon 
in otherwise healthy patients. 



FURTHER READINGS 

Albert DM et al (eds): Albert and Jakobicc's Principles and Practice of 
Ophthalmology, 3d ed. Philadelphia, Saunders, 2007 

D'Amico DJ: Clinical practice: Primary Retinal Detachment. N Engl 
J Med 359:2346, 2008 

ROSENFELD PJ et al: Ranibizumab for neovascular age-related macu- 
lar degeneration. N Engl J Med 355:1419, 2006 

RUTAR T et al: Ophthalmic manifestations of infections caused by 
the USA300 clone of community-associated methicillin-resistant 
Staphylococcus aureus. Ophthalmology 113:1455,2006 

TlNG AY et al: Genetics of age-related macular degeneration. Curr 
Opfn Ophthalmol 20:369, 2009 




Anil K. Lalwani 



Smell 193 

Definitions 1 93 

Physiology of Smell 1 93 

Disorders of the Sense of Smell 1 94 

Taste 1 96 

Definitions 1 96 

Physiology of Taste 1 96 

Disorders of the Sense of Taste 1 97 



Hearing 199 

Physiology of Hearing 1 99 

Genetic Causes of Hearing Loss 1 99 

Disorders of the Sense of Hearing 201 

Laboratory Assessment of Hearing 204 

Prevention 207 

Further Readings 207 



SMELL 

The sense of smell determines the flavor and palatability 
of food and drink and serves, along with the trigeminal 
system, as a monitor of inhaled chemicals, including 
dangerous substances such as natural gas, smoke, and air 
pollutants. Olfactory dysfunction affects ~1% of individ- 
uals younger than 60 years and more than one-half of 
the population beyond this age. 

DEFINITIONS 

Smell is the perception of odor by the nose. Taste is the 
perception of salty, sweet, sour, or bitter by the tongue. 
Related sensations during eating such as somatic sensa- 
tions of coolness, warmth, and irritation are mediated 
through the trigeminal, glossopharyngeal, and vagal affer- 
ents in the nose, oral cavity, tongue, pharynx, and larynx. 
Flavor is the complex interaction of taste, smell, and 
somatic sensation. Terms relating to disorders of smell 
include anosmia, an absence of the ability to smell; hypos- 
mia, a decreased ability to smell; hyperosmia, an increased 
sensitivity to an odorant; dysosmia, distortion in the per- 
ception of an odor; phantosmia, perception of an odorant 
where none is present; and agnosia, inability to classify, 
contrast, or identify odor sensations verbally, even though 
the ability to distinguish between odorants or to recog- 
nize them may be normal. An odor stimulus is referred 



193 



to as an odorant. Each category of smell dysfunction can 
be further subclassified as total (applying to all odorants) 
or partial (dysfunction of only select odorants) . 

PHYSIOLOGY OF SMELL 

The olfactory epithelium is located in the superior part of 
the nasal cavities and is highly variable in its distribution 
between individuals. Over time the olfactory epithelium 
loses its homogeneity, as small areas undergo metaplasia 
producing islands of respiratory-like epithelium. This 
process is thought to be secondary to insults from envi- 
ronmental toxins, bacteria, and viruses. The primary sen- 
sory neuron in the olfactory epithelium is the bipolar 
cell. The dendritic process of the bipolar cell has a bulb- 
shaped vesicle that projects into the mucous layer and 
bears six to eight cilia containing odorant receptors. On 
average, each bipolar cell elaborates 56 cm 2 (9 in. 2 ) of 
surface area to receive olfactory stimuli. These primary 
sensory neurons are unique among sensory systems in 
that they are short-lived, regularly replaced, and regener- 
ate and establish new central connections after injury. 
Basal stem cells, located on the basal surface of the olfac- 
tory epithelium, are the progenitors that differentiate 
into new bipolar cells (Fig. 18-1). 

Between 50 and 200 unmyelinated axons of receptor 
cells form the fila of the olfactory nerve; they pass through 
the cribriform plate to terminate within spherical masses 



194 




FIGURE 18-1 

Olfaction. Olfactory sensory neurons (bipolar cells) 
are embedded in a small area of specialized 
epithelium in the dorsal posterior recess of the 
nasal cavity. These neurons project axons to the 
olfactory bulb of the brain, a small ovoid structure 
that rests on the cribriform plate of the ethmoid 
bone. Odorants bind to specific receptors on olfac- 
tory cilia and initiate a cascade of action potential 
events that lead to the production of action poten- 
tials in the sensory axons. 



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of neuropil, termed glomeruli, in the olfactory bulb. 
Olfactory ensheathing cells, which have features resem- 
bling glia of both the central and peripheral nervous sys- 
tems, surround the axons along their course. The 
glomeruli are the focus of a high degree of convergence 
of information, since many more fibers enter than leave 
them. The main second-order neurons are mitral cells. 
The primary dendrite of each mitral cell extends into a 
single glomerulus. Axons of the mitral cells project along 
with the axons of adjacent tufted cells to the limbic sys- 
tem, including the anterior olfactory nucleus and the 
amygdala. Cognitive awareness of smell requires stimula- 
tion of the prepiriform cortex or amygdaloid nuclei. 

A secondary site of olfactory chemosensation is 
located in the epithelium of the vomeronasal organ, a 
tubular structure that opens on the ventral aspect of the 
nasal septum. In humans, this structure is rudimentary 
and nonfunctional, without central projections. Sensory 
neurons located in the vomeronasal organ detect 
pheromones, nonvolatile chemical signals that in lower 
mammals trigger innate and stereotyped reproductive 
and social behaviors, as well as neuroendocrine changes. 

The sensation of smell begins with introduction of an 
odorant to the cilia of the bipolar neuron. Most odor- 
ants are hydrophobic; as they move from the air phase of 
the nasal cavity to the aqueous phase of the olfactory 
mucous, they are transported toward the cilia by small 
water-soluble proteins called odorant-binding proteins and 
reversibly bind to receptors on the cilia surface. Binding 
leads to conformational changes in the receptor protein, 
activation of G protein-coupled second messengers, and 
generation of action potentials in the primary neurons. 
Intensity appears to be coded by the amount of firing in 
the afferent neurons. 

Olfactory receptor proteins belong to the large family 
of G protein-coupled receptors that also includes 
rhodopsins; (X- and (3-adrenergic receptors; muscarinic 



acetylcholine receptors; and neurotransmitter receptors 
for dopamine, serotonin, and substance P. In humans, 
there are 300—1000 olfactory receptor genes belonging 
to 20 different families located in clusters at >25 differ- 
ent chromosomal locations. Each olfactory neuron 
expresses only one or, at most, a few receptor genes, thus 
providing the molecular basis of odor discrimination. 
Bipolar cells that express similar receptors appear to be 
scattered across discrete spatial zones. These similar cells 
converge on a select few glomeruli in the olfactory 
bulb. The result is a potential spatial map of how we 
receive odor stimuli, much like the tonotopic organiza- 
tion of how we perceive sound. 

DISORDERS OF THE SENSE OF SMELL 

These are caused by conditions that interfere with the 
access of the odorant to the olfactory neuroepithelium 
(transport loss), injure the receptor region (sensory loss), 
or damage central olfactory pathways (neural loss) . Cur- 
rently no clinical tests exist to differentiate these differ- 
ent types of olfactory losses. Fortunately, the history of 
the disease provides important clues to the cause. The 
leading causes of olfactory disorders are summarized in 
Table 18-1; the most common etiologies are head 
trauma in children and young adults, and viral infections 
in older adults. 

Head trauma is followed by unilateral or bilateral 
impairment of smell in up to 15% of cases; anosmia is 
more common than hyposmia. Olfactory dysfunction is 
more common when trauma is associated with loss of 
consciousness, moderately severe head injury (grades 
II— V), and skull fracture. Frontal injuries and fractures 
disrupt the cribriform plate and olfactory axons that 
perforate it. Sometimes there is an associated cere- 
brospinal fluid (CSF) rhinorrhea resulting from a tearing 
of the dura overlying the cribriform plate and paranasal 



TABLE 18-1 



CAUSES OF OLFACTORY DYSFUNCTION j 


Transport Losses 


Neural Losses 


Allergic rhinitis 


AIDS 


Bacterial rhinitis and sinusitis 


Alcoholism 


Congenital abnormalities 


Alzheimer's disease 


Nasal neoplasms 


Cigarette smoke 


Nasal polyps 


Depression 


Nasal septal deviation 


Diabetes mellitus 


Nasal surgery 


Drugs/toxins 


Viral infections 


Huntington's chorea 


Sensory Losses 


Hypothyroidism 


Drugs 


Kallmann syndrome 


Neoplasms 


Malnutrition 


Radiation therapy 


Neoplasms 


Toxin exposure 


Neurosurgery 


Viral infections 


Parkinson's disease 




Trauma 




Vitamin B 12 deficiency 




Zinc deficiency 



sinuses. Anosmia may also follow blows to the occiput. 
Once traumatic anosmia develops, it is usually perma- 
nent; only 10% of patients ever improve or recover. Per- 
version of the sense of smell may occur as a transient 
phase in the recovery process. 

Viral infections can destroy the olfactory neuroep- 
ithelium, which is then replaced by respiratory epithe- 
lium. Parainfluenza virus type 3 appears to be especially 
detrimental to human olfaction. HIV infection is associ- 
ated with subjective distortion of taste and smell, which 
may become more severe as the disease progresses. The 
loss of taste and smell may play an important role in the 
development and progression of HIV-associated wasting. 
Congenital anosmias are rare but important. Kallmann 
syndrome is an X-linked disorder characterized by con- 
genital anosmia and hypogonadotropic hypogonadism 
resulting from a failure of migration from the olfactory 
placode of olfactory receptor neurons and neurons syn- 
thesizing gonadotropin-releasing hormone. Anosmia can 
also occur in albinos. The receptor cells are present but 
are hypoplastic, lack cilia, and do not project above the 
surrounding supporting cells. 

Meningiomas of the inferior frontal region are the most 
frequent neoplastic cause of anosmia; loss of smell may be 
the only neurologic abnormality. Rarely, anosmia can occur 
with gliomas of the frontal lobe. Occasionally, pituitary ade- 
nomas, craniopharyngiomas, suprasellar meningiomas, and 
aneurysms of the anterior part of the circle of Willis 
extend forward and damage olfactory structures. These 
tumors and hamartomas may also induce seizures with 
olfactory hallucinations, indicating involvement of the 
uncus of the temporal lobe. 

Olfactory dysfunction is common in a variety of neuro- 
logic diseases, including Alzheimer's disease, Parkinson's 



disease, amyotrophic lateral sclerosis, and multiple sclerosis. 
In Alzheimer's and Parkinson's, olfactory loss may be the 
first clinical sign of the disease. In Parkinson's disease, bilat- 
eral olfactory deficits occur more commonly than the car- 
dinal signs of the disorder such as tremor. In multiple scle- 
rosis, olfactory loss is related to lesions visible by MRI, in 
olfactory processing areas in the temporal and frontal lobes. 
Dysosmia, subjective distortions of olfactory percep- 
tion, may occur with intranasal diseases that partially 
impair smell or during recovery from a neurogenic 
anosmia. Most dysosmic disorders consist of disagreeable 
odors, sometimes accompanied by distortions of taste. 
Dysosmia also can occur with depression. 



195 



Approach to the Patient: 
DISORDERS OF THE SENSE OF SMELL 



Unilateral anosmia is rarely a complaint and is only 
recognized by testing of smell in each nasal cavity sepa- 
rately. Bilateral anosmia, on the other hand, brings 
patients to medical attention. Anosmic patients usually 
complain of a loss of the sense of taste even though 
their taste thresholds may be within normal limits. In 
actuality, they are complaining of a loss of flavor detec- 
tion, which is mainly an olfactory function. The physi- 
cal examination should include a thorough inspection 
of the ears, upper respiratory tract, and head and neck. 
A neurologic examination emphasizing the cranial 
nerves and cerebellar and sensorimotor function is 
essential. Any signs of depression should be noted. 

Sensory olfactory function can be assessed by sev- 
eral methods. The Odor Stix test uses a commercially 
available odor-producing magic marker— like pen held 
~8— 15 cm (3—6 in.) from the patient's nose. The 
30-cm alcohol test uses a freshly opened isopropyl 
alcohol packet held ~30 cm (12 in.) from the patient's 
nose. There is a commercially available scratch-and- 
sniff card containing three odors available for gross 
testing of olfaction. A superior test is the University 
of Pennsylvania Smell Identification Test (UPSIT). 
This consists of a 40-item, forced choice, scratch-and- 
sniff paradigm. For example, one of the items reads, 
"This odor smells most like (a) chocolate, (b) banana, 
(c) onion, or (d) fruit punch."The test is highly reliable, 
is sensitive to age and sex differences, and provides an 
accurate quantitative determination of the olfactory 
deficit. The UPSIT, which is a forced-choice test, can 
also be used to identify malingerers who typically 
report fewer correct responses than would be 
expected by chance. The average score for total anos- 
mics is slightly higher than that expected on the basis 
of chance because of the inclusion of some odorants 
that act by trigeminal stimulation. 






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Olfactory threshold testing is another method of 
assessing olfactory function. Following assessment of 
sensory olfactory function, the detection threshold 
for an odorant such as methyl ethyl carbinol is estab- 
lished using graduated concentrations for each side of 
the nose. Nasal resistance can also be measured with 
anterior rhinomanometry for each side of the nose. 

CT or MRI of the head is required to rule out 
paranasal sinusitis; neoplasms of the anterior cranial 
fossa, nasal cavity, or paranasal sinuses; or unsuspected 
fractures of the anterior cranial fossa. Bone abnormal- 
ities are best seen with CT. MRI is the most sensitive 
method to visualize olfactory bulbs, ventricles, and 
other soft tissue of the brain. Coronal CT is optimal 
for assessing cribriform plate, anterior cranial fossa, 
and sinus anatomy. 

Biopsy of the olfactory epithelium is possible. 
However, given the widespread degeneration of the 
olfactory epithelium and intercalation of respiratory 
epithelium in the olfactory area of adults -with no 
apparent olfactory dysfunction, biopsy results must be 
interpreted with caution. 



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Treatment: 

DISORDERS OF THE SENSE OF SMELL 



Therapy for patients with transport olfactory losses due 
to allergic rhinitis, bacterial rhinitis and sinusitis, polyps, 
neoplasms, and structural abnormalities of the nasal 
cavities can be undertaken with a high likelihood for 
improvement. Allergy management; antibiotic therapy; 
topical and systemic glucocorticoid therapy; and 
surgery for nasal polyps, deviation of the nasal septum, 
and chronic hyperplastic sinusitis are frequently effec- 
tive in restoring the sense of smell. 

There is no proven treatment for sensorineural olfac- 
tory losses. Fortunately, spontaneous recovery often 
occurs. Zinc and vitamin therapy (especially with vita- 
min A) are advocated by some. Profound zinc deficiency 
can produce loss and distortion of the sense of smell 
but is not a clinically important problem except in very 
limited geographic areas. The epithelial degeneration 
associated with vitamin A deficiency can cause anos- 
mia, but in western societies the prevalence of vitamin 
A deficiency is low. Exposure to cigarette smoke and 
other airborne toxic chemicals can cause metaplasia of 
the olfactory epithelium, and spontaneous recovery can 
occur if the insult is removed. Counseling of patients is 
therefore helpful in such cases. 

More than one-half of people older than 60 years suf- 
fer from olfactory dysfunction. No effective treatment 
exists for presbyosmia, but patients are often reassured 
to learn that this problem is common in their age group. 



In addition, early recognition and counseling can help 
patients to compensate for the loss of smell. The inci- 
dence of natural gas-related accidents is disproportion- 
ately high in the elderly, perhaps due in part to the 
gradual loss of smell. Mercaptan, the pungent odor in 
natural gas, is an olfactory stimulant that does not acti- 
vate taste receptors. Many elderly with olfactory dys- 
function experience a decrease in flavor sensation and 
find it necessary to hyperflavor food, usually by increas- 
ing the amount of salt in their diet. 



TASTE 

Compared with disorders of smell, gustatory disorders 
are uncommon. Loss of olfactory sensitivity is often 
accompanied by complaints of loss of the sense of taste, 
usually with normal detection thresholds for taste. 

DEFINITIONS 

Disturbances of the sense of taste may be categorized as 
total ageusia, total absence of gustatory function or 
inability to detect the qualities of sweet, salt, bitter, or 
sour; partial ageusia, ability to detect some but not all of 
the qualitative gustatory sensations; specific ageusia, inabil- 
ity to detect the taste quality of certain substances; total 
hypogeusia, decreased sensitivity to all tastants; partial 
hypogeusia, decreased sensitivity to some tastants; and dys- 
geusia or phantogeusia, distortion in the perception of a 
tastant, i.e., the perception of the wrong quality when a 
tastant is presented or the perception of a taste when 
there has been no tastant ingested. Confusion between 
sour and bitter, and less commonly between salty and 
bitter, may represent a semantic misunderstanding or 
have a true pathophysiologic basis. It may be possible to 
differentiate between the loss of flavor recognition in 
patients with olfactory losses who complain of a loss of 
taste as well as smell by asking if they are able to taste 
sweetness in sodas, saltiness in potato chips, etc. 

PHYSIOLOGY OF TASTE 

The taste receptor cells are located in the taste buds, 
spherical groups of cells arranged in a pattern resem- 
bling the segments of a citrus fruit (Fig. 18-2). At the 
surface, the taste bud has a pore into which microvilli of 
the receptor cells project. Unlike the olfactory system, 
the receptor cell is not the primary neuron. Instead, gus- 
tatory afferent nerve fibers contact individual taste 
receptor cells. The papillae he along the lateral margin 
and dorsum of the tongue; at the junction of the dor- 
sum and the base of the tongue; and in the palate, 
epiglottis, larynx, and esophagus. 



Chorda tympan 
nerve (VII) 



Glossopharyngeal 
nerve (IX) 




Taste 
-bud 



Fungiform 



Taste pore 




Epithelial cell 
Taste cell 

Basal cell 

Gustatory afferent 
nerve 



FIGURE 18-2 

Taste. A The taste buds of the anterior two-thirds of the 
tongue are innervated by the gustatory fibers that travel in a 
branch of the facial nerve (VII) called the chorda tympani. The 
taste buds of the posterior third of the tongue are innervated 
by gustatory fibers that travel in the lingual branch of the 
glossopharyngeal nerve (IX). [Adapted from ER Kandel et al 
(eds): Principles of Neural Science, 4th ed., New York, 
McGraw-Hill, 2000; with permission.] B. The main types of 
taste papillae are shown in schematic cross sections. Each 
type predominates in specific areas of the tongue, as indi- 
cated by the arrows from A. C. Each taste bud contains 
50-150 taste cells that extend from the base of the taste bud 
to the taste pore, where the apical microvilli of taste cells 
have contact with tastants dissolved in saliva and taste pore 
mucus. Access of tastants to the basolateral regions of these 
cells is generally prevented by tight junctions between taste 
cells. Taste cells are short-lived cells that are replaced from 
stem cells at the base of the taste bud. Three types of taste 
cells in each taste bud (light cells, dark cells, and intermedi- 
ate cells) may represent different stages of differentiation or 
different cell lineages. Taste stimuli, detected at the apical 
end of the taste cell, induce action potentials that cause the 
release of neurotransmitter at synapses formed at the base 
of the taste cell with gustatory fibers that transmit signals to 
the brain. 



Tastants gain access to the receptor cells through the 
taste pore. Four classes of taste have been traditionally 
recognized: sweet, salt, sour, and bitter, and more 
recently "umami" (monosodium glutamate, disodium 
gluanylate, disodium inosinate). Tastants enter the taste 
pore in a solution and initiate transduction by either 
activating receptors coupled to G-proteins or by directly 
activating ion channels on the microvillae within the 
taste bud. Individual gustatory afferent fibers almost 
always respond to a number of different chemicals. As 
with olfaction and other sensory systems, intensity 
appears to be encoded by the quantity of neural activity. 

The sense of taste is mediated through the facial, 
glossopharyngeal, and vagal nerves. The chorda tympani 
branch of the facial nerve subserves taste from the ante- 
rior two-thirds of the tongue. The posterior third of the 
tongue is supplied by the lingual branch of the glos- 
sopharyngeal nerve. Afferents from the palate travel with 
the greater superficial petrosal nerve to the geniculate 
ganglion and then via the facial nerve to the brainstem. 
The internal branch of the superior laryngeal nerve of 
the vagus nerve contains the taste afferents from the lar- 
ynx, including the epiglottis and esophagus. 

The central connections of the nerves terminate in 
the brainstem in the nucleus of the tractus solitarius.The 
central pathway from the nucleus of the tractus solitarius 
projects to the ipsilateral parabrachial nuclei of the pons. 
Two divergent pathways project from the parabrachial 
nuclei. One ascends to the gustatory relay in the dorsal 
thalamus, synapses, and continues to the cortex of the 
insula. There is also evidence for a direct pathway from 
the parabrachial nuclei to the cortex. (Olfaction and 
gustation appear to be unique among sensory systems in 
that at least some fibers bypass the thalamus.) The other 
pathway from the parabrachial nuclei goes to the ventral 
forebrain, including the lateral hypothalamus, substantia 
innominata, central nucleus of the amygdala, and the 
stria terminalis. 

DISORDERS OF THE SENSE OF TASTE 

Disorders of the sense of taste are caused by conditions 
that interfere with the access of the tastant to the recep- 
tor cells in the taste bud (transport loss), injure receptor 
cells (sensory loss), or damage gustatory afferent nerves 
and central gustatory pathways (neural loss) (Table 18-2). 
Transport gustatory losses result from xerostomia due to 
many causes, including Sjogren's syndrome, radiation 
therapy, heavy-metal intoxication, and bacterial coloniza- 
tion of the taste pore. Sensory gustatory losses are caused by 
inflammatory and degenerative diseases in the oral cavity; 
a vast number of drugs, particularly those that interfere 
with cell turnover such as antithyroid and antineoplastic 
agents; radiation therapy to the oral cavity and pharynx; 
viral infections; endocrine disorders; neoplasms; and aging. 
Neural gustatory losses occur with neoplasms, trauma, and 



197 






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CAUSES OF GUSTATORY DYSFUNCTION I 


Transport Gustatory Losses 


Neural Gustatory Losses 


Drugs 


Diabetes mellitus 


Heavy-metal intoxication 


Hypothyroidism 


Radiation therapy 


Oral neoplasms 


Sjogren's syndrome 


Oral surgery 


Xerostomia 


Radiation therapy 


Sensory Gustatory Losses 


Renal disease 


Aging 


Stroke and other CNS 


Candidiasis 


disorders 


Drugs (antithyroid and 


Trauma 


antineoplastic) 


Upper respiratory tract 


Endocrine disorders 


infections 


Oral neoplasms 




Pemphigus 




Radiation therapy 




Viral infections (especially 




with herpes viruses) 





Approach to the Patient: 
DISORDERS OF THE SENSE OF TASTE 



surgical procedures in which the gustatory afferents are 
injured. Taste buds degenerate when their gustatory affer- 
ents are transected but remain when their somatosensory 
afferents are severed. Patients with renal disease have 
increased thresholds for sweet and sour tastes, which 
resolves with dialysis. 

A side effect of medication is the single most com- 
mon cause of taste dysfunction in clinical practice. 
Xerostomia, regardless of the etiology, can be associated 
with taste dysfunction. It is associated with poor oral 
clearance and poor dental hygiene and can adversely 
affect the oral mucosa, all leading to dysgeusia. However, 
severe salivary gland failure does not necessarily lead to 
taste complaints. Xerostomia, the use of antibiotics or 
glucocorticoids, or immunodeficiency can lead to over- 
growth of Candida; overgrowth alone, without thrush or 
overt signs of infection, can be associated with bad taste 
or hypogeusia. When taste dysfunction occurs in a 
patient at risk for fungal overgrowth, a trial of nystatin 
or other antifungal medication is warranted. 

Upper respiratory infections and head trauma can 
lead to both smell and taste dysfunction; taste is more 
likely to improve than smell. The mechanism of taste 
disturbance in these situations is not well understood. 
Trauma to the chorda tympani branch of the facial 
nerve during middle ear surgery or third molar extrac- 
tions is relatively common and can cause dysgeusia. 
Bilateral chorda tympani injuries are usually associated 
with hypogeusia, whereas unilateral lesions produce only 
limited symptoms. 

As noted above, aging itself may be associated with 
reduced taste sensitivity. The taste dysfunction may be 
limited to a single compound and may be mild. 



Patients who complain of loss of taste should be eval- 
uated for both gustatory and olfactory function. Clin- 
ical assessment of taste is not as well developed or 
standardized as that of smell. The first step is to per- 
form suprathreshold whole-mouth taste testing for 
quality, intensity, and pleasantness perception of four 
taste qualities: sweet, salty, sour, and bitter. Most com- 
monly used reagents for taste testing are sucrose, citric 
acid or hydrochloric acid, caffeine or quinine (sulfate 
or hydrochloride), and sodium chloride. The taste 
stimuli should be freshly prepared and have similar 
viscosity. For quantification, detection thresholds are 
obtained by applying graduated dilutions to the 
tongue quadrants or by whole-mouth sips. Electric 
taste testing (electrogustometry) is used clinically to 
identify taste deficits in specific quadrants of the 
tongue. Regional gustatory testing may also be per- 
formed to assess for the possibility of loss localized to 
one or several receptor fields as a result of a periph- 
eral or central lesion. The history of the disease and 
localization studies provide important clues to the 
causes of the taste disturbance. For example, absence 
of taste on the anterior two-thirds of the tongue asso- 
ciated with a facial paralysis indicates that the lesion is 
proximal to the juncture of the chorda tympani 
branch with the facial nerve in the mastoid. 



D Treatment: 

fr DISORDERS OF THE SENSE OF TASTE 

Treatment of gustatory disorders is limited. No effective 
therapies exist for the sensorineural disorders of taste. 
Altered taste due to surgical stretch injury of the chorda 
tympani nerve usually improves within 3-4 months, 
while dysfunction is usually permanent with transection 
of the nerve. Taste dysfunction following trauma may 
resolve spontaneously without intervention and is more 
likely to do so than posttraumatic smell dysfunction. 
Idiopathic alterations of taste sensitivity usually remain 
stable or worsen; zinc and vitamin therapy are of 
unproven value. Directed therapy to address factors that 
affect taste perception can be of value. Xerostomia can 
be treated with artificial saliva, providing some benefit 
to patients with a disturbed salivary milieu. Oral pilo- 
carpine may be beneficial for a variety of forms of xeros- 
tomia. Appropriate treatment of bacterial and fungal 
infections of the oral cavity can be of great help in 
improving taste function. Taste disturbance related to 
drugs can often be resolved by changing the prescribed 
medication. 



HEARING 



Hearing loss is one of the most common sensory disor- 
ders in humans and can present at any age. Nearly 10% 
of the adult population has some hearing loss, and one- 
third of individuals >65 years have a hearing loss of suf- 
ficient magnitude to require a hearing aid. 

PHYSIOLOGY OF HEARING 

(Fig. 18-3) The function of the external and middle ear 
is to amplify sound to facilitate mechanotransduction by 
hair cells in the inner ear. Sound waves enter the exter- 
nal auditory canal and set the tympanic membrane in 
motion, which in turn moves the malleus, incus, and 
stapes of the middle ear. Movement of the footplate of 
the stapes causes pressure changes in the fluid-filled 
inner ear eliciting a traveling wave in the basilar mem- 
brane of the cochlea. The tympanic membrane and the 
ossicular chain in the middle ear serve as an impedance- 
matching mechanism, improving the efficiency of 
energy transfer from air to the fluid-filled inner ear. 

Stereocilia of the hair cells of the organ of Corti, 
which rests on the basilar membrane, are in contact with 
the tectorial membrane and are deformed by the travel- 
ing wave. A point of maximal displacement of the basilar 
membrane is determined by the frequency of the stimu- 
lating tone. High-frequency tones cause maximal dis- 
placement of the basilar membrane near the base of the 
cochlea. As the frequency of the stimulating tone 
decreases, the point of maximal displacement moves 
toward the apex of the cochlea. 

The inner and outer hair cells of the organ of 
Corti have different innervation patterns, but both are 



mechanoreceptors.The afferent innervation relates prin- 
cipally to the inner hair cells, and the efferent innerva- 
tion relates principally to outer hair cells. The motility 
of the outer hair cells alters the micromechanics of the 
inner hair cells, creating a cochlear amplifier, which 
explains the exquisite sensitivity and frequency selectiv- 
ity of the cochlea. 

Beginning in the cochlea, the frequency specificity is 
maintained at each point of the central auditory pathway: 
dorsal and ventral cochlear nuclei, trapezoid body, superior 
olivary complex, lateral lemniscus, inferior colliculus, 
medial geniculate body, and auditory cortex. At low fre- 
quencies, individual auditory nerve fibers can respond 
more or less synchronously with the stimulating tone. At 
higher frequencies, phase-locking occurs so that neurons 
alternate in response to particular phases of the cycle of the 
sound wave. Intensity is encoded by the amount of neural 
activity in individual neurons, the number of neurons that 
are active, and the specific neurons that are activated. 

GENETIC CAUSES OF HEARING LOSS 

More than half of childhood hearing impairment is 
thought to be hereditary; hereditary hearing impair- 
ment (HHI) can also manifest later in life. HHI may 
be classified as either nonsyndromic, when hearing loss is 
the only clinical abnormality, or syndromic, when hearing 
loss is associated with anomalies in other organ systems. 
Nearly two-thirds of HHIs are nonsyndromic, and the 
remaining one-third are syndromic. Between 70 and 80% 
of nonsyndromic HHI is inherited in an autosomal reces- 
sive manner and designated DFNB; another 15—20% is 
autosomal dominant (DFNA). Less than 5% is X-linked or 
maternally inherited via the mitochondria. 



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External acoustic 
meatus 



Auricle or 
pinna 



Middle ear 

I 



Stapes 
Incus 
Malleus 



Semicircular canals 
Cochlea 




Vestibulocochlear 
nerve 



Inner 
ear 



Bony labyrinth 
(contains perilymph) 

Membranous labyrinth 
(contains endolymph) 

Ampulla of 
semicircular canal 



External Tympanic 
acoustic membrane 
canal 



Lobe 



Eustachian tube 



A External ear 

FIGURE 18-3 

Ear anatomy. A. Drawing of modified coronal section through 
external ear and temporal bone, with structures of the middle 




Cochlea 



Vestibule 



B 



and inner ear demonstrated. B. High-resolution view of 
inner ear. 



200 Nearly 100 loci harboring genes for nonsyndromic 
HHI have been mapped, with equal numbers of domi- 
nant and recessive modes of inheritance; numerous genes 
have now been cloned (Table 18-3). The hearing genes 
fall into the categories of structural proteins (MYH9, 
MY07A, MY015, TECTA, DIAPH1), transcription 



factors (POU3F4, POU4F3), ion channels (KCNQ4, 
SLC26A4), and gap junction proteins (GJB2, GJB3, 
GJB6). Several of these genes, including connexin 26 
(GJB2), TECTA, andTMCl, cause both autosomal dom- 
inant and recessive forms of nonsyndromic HHI. In gen- 
eral, the hearing loss associated with dominant genes has 



TABLE 18-3 



HEREDITARY HEARING IMPAIRMENT GENES 



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QJ 



DESIGNATION 


GENE 


FUNCTION 


Autosomal Dominant 




CRYM 


Thyroid hormone binding protein 


DFNA1 


DIAPH1 


Cytoskeletal protein 


DFNA2 


GJB3 (Cx31) 


Gap junctions 


DFNA2 


KCNQ4 


Potassium channel 


DFNA3 


GJB2 (Cx26) 


Gap junctions 


DFNA3 


GJB6 (Cx30) 


Gap junctions 


DFNA4 


MYH14 


Class II nonmuscle myosin 


DFNA5 


DFNA5 


Unknown 


DFNA6/14/38 


WFS 


Transmembrane protein 


DFNA8/12 


TECTA 


Tectorial membrane protein 


DFNA9 


COCH 


Unknown 


DFNA10 


EYA4 


Developmental gene 


DFNA1 1 


MY07A 


Cytoskeletal protein 


DFNA13 


COL11A2 


Cytoskeletal protein 


DFNA15 


POU4F3 


Transcription factor 


DFNA17 


MYH9 


Cytoskeletal protein 


DFNA20/26 


ACTG1 


Cytoskeletal protein 


DFNA22 


MY06 


Unconventional myosin 


DFNA28 


TFCP2L3 


Transcription factor 


DFNA36 


TMC1 


Transmembrane protein 


DFNA48 


MY01A 


Unconventional myosin 


Autosomal Recessive 








SLC26A5 (Prestin) 


Motor protein 


DFNB1 


GJB2 (CX26) 


Gap junction 




GJB6(CX30) 


Gap junction 


DFNB2 


MY07A 


Cytoskeletal protein 


DFNB3 


MY015 


Cytoskeletal protein 


DFNB4 


PDS(SLC26A4) 


Chloride/iodide transporter 


DFNB6 


TMIE 


Transmembrane protein 


DFNB7/B11 


TMC1 


Transmembrane protein 


DFNB9 


OTOF 


Trafficking of membrane vesicles 


DFNB8/10 


TMPRSS3 


Transmembrane serine protease 


DFNB12 


CDH23 


Intercellular adherence protein 


DFNB16 


STRC 


Stereocilia protein 


DFNB18 


USH1C 


Unknown 


DFNB21 


TECTA 


Tectorial membrane protein 


DFNB22 


OTOA 


Gel attachement to nonsensory cell 


DFNB23 


PCDH15 


Morphogenesis and cohesion 


DFNB28 


TRIOBP 


Cytoskeletal-organizing protein 


DFNB29 


CLDN14 


Tight junctions 


DFNB30 


MY03A 


Hybrid motor-signaling myosin 


DFNB31 


WHRN 


PDZ domain-containing protein 


DFNB36 


ESPN 


Ca-insensitive actin-bundling protein 


DFNB37 


MY06 


Unconventional myosin 


DFNB67 


TMHS 


Unknown function; tetraspan protein 



its onset in adolescence or adulthood and varies in sever- 
ity, whereas the hearing loss associated with recessive 
inheritance is congenital and profound. Connexin 26 is 
particularly important because it is associated with nearly 
20% of cases of childhood deafness. Two frame-shift 
mutations, 35delG and 167delT, account for >50% of the 
cases; however, screening for these two mutations alone is 
insufficient to diagnose GJB2-related recessive deafness. 
The 167delT mutation is highly prevalent in Ashkenazi 
Jews; ~1 in 1765 individuals in this population are 
homozygous and affected. The hearing loss can also vary 
among the members of the same family, suggesting that 
other genes or factors influence the auditory phenotype. 

The contribution of genetics to presbycusis (see 
later) is also becoming better understood. In addition to 
GJB2, several other nonsyndromic genes are associated 
with hearing loss that progresses with age. Sensitivity to 
aminoglycoside ototoxicity can be maternally transmit- 
ted through a mitochondrial mutation. Susceptibility to 
noise-induced hearing loss may also be genetically 
determined. 

There are >400 syndromic forms of hearing loss. 
These include Usher syndrome (retinitis pigmentosa and 
hearing loss),Waardenburg syndrome (pigmentary abnor- 
mality and hearing loss), Pendred syndrome (thyroid 
organification defect and hearing loss), Alport syndrome 
(renal disease and hearing loss),Jervell and Lange-Nielsen 



syndrome (prolonged QT interval and hearing loss), 201 
neurofibromatosis type 2 (bilateral acoustic schwan- 
noma), and mitochondrial disorders [mitochondrial 
encephalopathy, lactic acidosis, and stroke -like episodes 
(MELAS); myoclonic epilepsy and ragged red fibers 
(MERRF) ; progressive external ophthalmoplegia (PEO)] 
(Table 18-4;. 



DISORDERS OF THE SENSE OF HEARING 

Hearing loss can result from disorders of the auricle, 
external auditory canal, middle ear, inner ear, or central 
auditory pathways (Fig. 18-4). In general, lesions in the 
auricle, external auditory canal, or middle ear cause conductive 
hearing losses, whereas lesions in the inner ear or eighth nerve 
cause sensorineural hearing losses. 



Conductive Hearing Loss 

This results from obstruction of the external auditory 
canal by cerumen, debris, and foreign bodies; swelling of 
the lining of the canal; atresia or neoplasms of the canal; 
perforations of the tympanic membrane; disruption of 
the ossicular chain, as occurs with necrosis of the long 
process of the incus in trauma or infection; otosclerosis; 
or fluid, scarring, or neoplasms in the middle ear. Rarely, 









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TABLE 18-4 



SYNDROMIC HEREDITARY HEARING IMPAIRMENT GENES 



SYNDROME 


GENE 


FUNCTION 


Alport syndrome 


COL4A3-5 


Cytoskeletal protein 


BOR syndrome 


EYA1 


Developmental gene 




SIX1 


Developmental gene 


Jervell and Lange-Nielsen 


KVLQT1 


Delayed rectifier K + channel 


syndrome 


KCNE1 


Delayed rectifier K + channel 


Norrie disease 


Norrin 


Cell-cell interactions 


Pendred syndrome 


SLC26A4 


Chloride/iodide transporter 


Treacher Collins 


TCOF1 


Nucleolar-cytoplasmic transport 


Usher syndrome 


MY07A 


Cytoskeletal protein 




USH1C 


Unknown 




CDH23 


Intercellular adherence protein 




PCDH15 


Cell adhesion molecule 




SANS 


Harmonin associated protein 




USH2A 


Cell adhesion molecule 




VLGR1 


G protein-coupled receptor 




USH3 


Unknown 


WStypel, III 


PAX3 


Transcription factor 


WS type II 


MITF 


Transcription factor 




SLUG 


Transcription factor 


WS type IV 


EDNRB 


Endothelin-B receptor 




EDN3 


Endothelin-B receptor ligand 




SOX10 


Transcription factor 



Note: BOR, branch io-oto-renal syndrome; WS, Waardenburg syndrome. 



202 



ST 
o' 



o 






Cerumen impaction 

TM perforation 

Cholesteatoma 

SOM 

AOM 

External auditory 

canal atresia/ 

stenosis 
Eustachian tube 

dysfunction 
Tympanosclerosis 



Hearing Loss 
1 



History 



Otologic examination 



(f normalj) 



Pure tone and 
speech audiometry 



Conductive HL 



Mixed HL 



Impedence audiometry 





Impedence audiometry 



(^normaf) (abnormal) 



Otosclerosis 


AOM 


Cerumen 


SOM 


impaction 


TM perforation* 


Ossicular 


Eustachian tube 


fixation 


dysfunction 


Cholesteatoma* 


Cerumen 


Temporal bone 


impaction 


trauma* 


Cholesteatoma* 




Temporal bone 




trauma* 




Ossicular 




discontinuity* 




Middle ear tumor* 






Stapes gusher 
syndrome* 

Inner ear 
malformation* 

Otosclerosis 

Temporal bone 
trauma* 






AOM 

TM perforation* 
Cholesteatoma* 
Temporal bone 
trauma* 
Middle ear tumors* 
glomus 
tympanicum 
glomus jugulare 



FIGURE 18-4 

An algorithm for the approach to hearing loss. HL, hear- 
ing loss; SNHL, sensorineural hearing loss; TM, tympanic 



l— bINML — l 



Acute 
Asymmetric/symmetric 



Chronic 



CNS infectiont 
Tumorsf 

Cerebellopontine 
angle 

CNS 
Strokef 
Trauma* 



Asymmetric 




Symmetric 



MRI/BAER 




Inner ear 
malformation* 
Presbycusis 
Noise exposure 
Radiation therapy 



Endolymphatic hydrops 
Labyrinthitis* 
Perilymphatic fistula* 
Radiation therapy 



Labyrinthitis* 

Inner ear malformations* 

Cerebellopontine angle tumors 

Arachnoid cyst; facial nerve tumor; 

lipoma; meningioma; vestibular 

schwannoma 
Multiple sclerosis 1 ' 



membrane; SOM, serous otitis media; AOM, acute otitis 
media; *, CT scan of temporal bone; f, MRI scan. 



inner-ear malformations may present as conductive 
hearing loss beginning in adulthood. 

Cholesteatoma, stratified squamous epithelium in the 
middle ear or mastoid, occurs frequently in adults. This is 
a benign, slowly growing lesion that destroys bone and 
normal ear tissue. Theories of pathogenesis include trau- 
matic implantation and invasion, immigration and inva- 
sion through a perforation, and metaplasia following 
chronic infection and irritation. On examination, there is 
often a perforation of the tympanic membrane filled with 
cheesy white squamous debris. A chronically draining ear 
that fails to respond to appropriate antibiotic therapy 
should raise suspicion of a cholesteatoma. Conductive 
hearing loss secondary to ossicular erosion is common. 
Surgery is required to remove this destructive process. 

Conductive hearing loss with a normal ear canal and 
intact tympanic membrane suggests ossicular pathology. 
Fixation of the stapes from otosclerosis is a common cause 
of low-frequency conductive hearing loss. It occurs equally 
in men and women and is inherited as an autosomal 
dominant trait with incomplete penetrance. Hearing 



impairment usually presents between the late teens to 
the forties. In women, the otosclerotic process is acceler- 
ated during pregnancy, and the hearing loss is often first 
noticeable at this time. A hearing aid or a simple outpa- 
tient surgical procedure (stapedectomy) can provide ade- 
quate auditory rehabilitation. Extension of otosclerosis 
beyond the stapes footplate to involve the cochlea 
(cochlear otosclerosis) can lead to mixed or sensorineural 
hearing loss. Fluoride therapy to prevent hearing loss 
from cochlear otosclerosis is of uncertain value. 

Eustachian tube dysfunction is extremely common in 
adults and may predispose to acute otitis media (AOM) 
or serous otitis media (SOM) . Trauma, AOM, or chronic 
otitis media are the usual factors responsible for tympanic 
membrane perforation. While small perforations often 
heal spontaneously, larger defects usually require surgical 
intervention. Tympanoplasty is highly effective (>90%) in 
the repair of tympanic membrane perforations. Otoscopy 
is usually sufficient to diagnose AOM, SOM, chronic 
otitis media, cerumen impaction, tympanic membrane 
perforation, and eustachian tube dysfunction. 



Sensorineural Hearing Loss 

Damage to the hair cells of the organ of Corti may be 
caused by intense noise, viral infections, ototoxic drugs 
(e.g., salicylates, quinine and its synthetic analogues, 
aminoglycoside antibiotics, loop diuretics such as 
furosemide and ethacrynic acid, and cancer chemothera- 
peutic agents such as cisplatin), fractures of the temporal 
bone, meningitis, cochlear otosclerosis (see earlier), 
Meniere's disease, and aging. Congenital malformations 
of the inner ear may be the cause of hearing loss in 
some adults. Genetic predisposition alone or in concert 
with environmental exposures may also be responsible. 

Presbycusis (age-associated hearing loss) is the most 
common cause of sensorineural hearing loss in adults. In 
the early stages, it is characterized by symmetric, gentle 
to sharply sloping high-frequency hearing loss. With 
progression, the hearing loss involves all frequencies. 
More importantly, the hearing impairment is associated 
with significant loss in clarity. There is a loss of discrimi- 
nation for phonemes, recruitment (abnormal growth of 
loudness), and particular difficulty in understanding 
speech in noisy environments. Hearing aids may provide 
limited rehabilitation once the word recognition score 
deteriorates below 50%. Cochlear implants are the treat- 
ment of choice when hearing aids prove inadequate, 
even when hearing loss is incomplete. 

Meniere's disease is characterized by episodic vertigo, 
fluctuating sensorineural hearing loss, tinnitus, and aural 
fullness. Tinnitus and/or deafness may be absent during 
the initial attacks of vertigo, but invariably appear as the 
disease progresses and increase in severity during acute 
attacks. The annual incidence of Meniere's disease is 
0.5—7.5 per 1000; onset is most frequently in the fifth 
decade of life but may also occur in young adults or the 
elderly. Histologically, there is distention of the endolym- 
phatic system (endolymphatic hydrops) leading to degen- 
eration of vestibular and cochlear hair cells. This may 
result from endolymphatic sac dysfunction secondary to 
infection, trauma, autoimmune disease, inflammatory 
causes, or tumor; an idiopathic etiology constitutes the 
largest category and is most accurately referred to as 
Meniere's disease. Although any pattern of hearing loss 
can be observed, typically, low-frequency unilateral sen- 
sorineural hearing impairment is present. MRI should be 
obtained to exclude retrocochlear pathology such as a 
cerebellopontine angle tumor or demyelinating disorder. 
Therapy is directed toward the control of vertigo. A 
low-salt diet is the mainstay of treatment for control of 
rotatory vertigo. Diuretics, a short course of glucocorti- 
coids, and intratympanic gentamicin may also be useful 
adjuncts in recalcitrant cases. Surgical therapy of vertigo 
is reserved for unresponsive cases and includes endolym- 
phatic sac decompression, labyrinthectomy, and vestibular 
nerve section. Both labyrinthectomy and vestibular nerve 
section abolish rotatory vertigo in >90% of patients. 



Unfortunately, there is no effective therapy for hearing 
loss, tinnitus, or aural fullness from Meniere's disease. 

Sensorineural hearing loss may also result from any 
neoplastic, vascular, demyelinating, infectious, or degen- 
erative disease or trauma affecting the central auditory 
pathways. HIV leads to both peripheral and central 
auditory system pathology and is associated with sen- 
sorineural hearing impairment. 

A finding of conductive and sensory hearing loss in 
combination is termed mixed hearing loss. Mixed hearing 
losses are due to pathology of both the middle and inner 
ear, as can occur in otosclerosis involving the ossicles and the 
cochlea, head trauma, chronic otitis media, cholesteatoma, 
middle ear tumors, and some inner ear malformations. 

Trauma resulting in temporal bone fractures may be 
associated with conductive, sensorineural, or mixed 
hearing loss. If the fracture spares the inner ear, there 
may simply be conductive hearing loss due to rupture of 
the tympanic membrane or disruption of the ossicular 
chain. These abnormalities can be surgically corrected. 
Profound hearing loss and severe vertigo are associated 
with temporal bone fractures involving the inner ear. A 
perilymphatic fistula associated with leakage of inner- 
ear fluid into the middle ear can occur and may require 
surgical repair. An associated facial nerve injury is not 
uncommon. CT is best suited to assess fracture of the 
traumatized temporal bone, evaluate the ear canal, and 
determine the integrity of the ossicular chain and the 
involvement of the inner ear. CSF leaks that accompany 
temporal bone fractures are usually self-limited; the 
value of prophylactic antibiotics is uncertain. 

Tinnitus is defined as the perception of a sound when 
there is no sound in the environment. It may have a 
buzzing, roaring, or ringing quality and may be pulsatile 
(synchronous with the heartbeat). Tinnitus is often associ- 
ated with either a conductive or sensorineural hearing 
loss. The pathophysiology of tinnitus is not well under- 
stood. The cause of the tinnitus can usually be determined 
by finding the cause of the associated hearing loss. Tinnitus 
may be the first symptom of a serious condition such as a 
vestibular schwannoma. Pulsatile tinnitus requires evalua- 
tion of the vascular system of the head to exclude vascular 
tumors such as glomus jugulare tumors, aneurysms, and 
stenotic arterial lesions; it may also occur with SOM. 



Approach to the Patient: 

DISORDERS OF THE SENSE OF HEARING 

The goal in the evaluation of a patient with auditory 
complaints is to determine (1) the nature of the hearing 
impairment (conductive vs. sensorineural vs. mixed), (2) 
the severity of the impairment (mild, moderate, severe, 
profound), (3) the anatomy of the impairment (external 
ear, middle ear, inner ear, or central auditory pathway), 



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and (4) the etiology. The history should elicit character- 
istics of the hearing loss, including the duration of deaf- 
ness, unilateral vs. bilateral involvement, nature of onset 
(sudden vs. insidious), and rate of progression (rapid vs. 
slow). Symptoms of tinnitus, vertigo, imbalance, aural 
fullness, otorrhea, headache, facial nerve dysfunction, 
and head and neck paresthesias should be noted. Infor- 
mation regarding head trauma, exposure to ototoxins, 
occupational or recreational noise exposure, and family 
history of hearing impairment may also be important. A 
sudden onset of unilateral hearing loss, with or without 
tinnitus, may represent a viral infection of the inner ear 
or a stroke. Patients with unilateral hearing loss (sensory 
or conductive) usually complain of reduced hearing, 
poor sound localization, and difficulty hearing clearly 
with background noise. Gradual progression of a hear- 
ing deficit is common with otosclerosis, noise-induced 
hearing loss, vestibular schwannoma, or Meniere's dis- 
ease. Small vestibular schwannomas typically present 
with asymmetric hearing impairment, tinnitus, and 
imbalance (rarely vertigo); cranial neuropathy, in partic- 
ular of the trigeminal or facial nerve, may accompany 
larger tumors. In addition to hearing loss, Meniere's dis- 
ease may be associated with episodic vertigo, tinnitus, 
and aural fullness. Hearing loss with otorrhea is most 
likely due to chronic otitis media or cholesteatoma. 

Examination should include the auricle, external ear 
canal, and tympanic membrane. The external ear canal 
of the elderly is often dry and fragile; it is preferable to 
clean cerumen with wall-mounted suction and ceru- 
men loops and to avoid irrigation. In examining the 
eardrum, the topography of the tympanic membrane 
is more important than the presence or absence of the 
light reflex. In addition to the pars tensa (the lower 
two-thirds of the eardrum), the pars flaccida above the 
short process of the malleus should also be examined 
for retraction pockets that may be evidence of chronic 
eustachian tube dysfunction or cholesteatoma. Insuf- 
flation of the ear canal is necessary to assess tympanic 
membrane mobility and compliance. Careful inspec- 
tion of the nose, nasopharynx, and upper respiratory 
tract is indicated. Unilateral serous effusion should 
prompt a fiberoptic examination of the nasopharynx 
to exclude neoplasms. Cranial nerves should be evalu- 
ated with special attention to facial and trigeminal 
nerves, which are commonly affected with tumors 
involving the cerebellopontine angle. 

The Rinne and Weber tuning fork tests, with a 
512-Hz tuning fork, are used to screen for hearing 
loss, differentiate conductive from sensorineural hear- 
ing losses, and to confirm the findings of audiologic 
evaluation. Rinne s test compares the ability to hear by 
air conduction with the ability to hear by bone con- 
duction. The tines of a vibrating tuning fork are held 
near the opening of the external auditory canal, and 



then the stem is placed on the mastoid process; for 
direct contact, it may be placed on teeth or dentures. 
The patient is asked to indicate whether the tone is 
louder by air conduction or bone conduction. Nor- 
mally, and in the presence of sensorineural hearing 
loss, a tone is heard louder by air conduction than by 
bone conduction; however, with conductive hearing 
loss of >30 dB (see Audiologic Assessment, below), the 
bone-conduction stimulus is perceived as louder than 
the air-conduction stimulus. For the Weber test, the 
stem of a vibrating tuning fork is placed on the head 
in the midline and the patient asked whether the tone 
is heard in both ears or better in one ear than in the 
other. With a unilateral conductive hearing loss, the 
tone is perceived in the affected ear. With a unilateral 
sensorineural hearing loss, the tone is perceived in the 
unaffected ear. A 5-dB difference in hearing between 
the two ears is required for lateralization. 



LABORATORY ASSESSMENT OF HEARING 
Audiologic Assessment 

The minimum audiologic assessment for hearing loss 
should include the measurement of pure tone air- 
conduction and bone-conduction thresholds, speech 
reception threshold, discrimination score, tympanome- 
try, acoustic reflexes, and acoustic-reflex decay. This test 
battery provides a screening evaluation of the entire 
auditory system and allows one to determine whether 
further differentiation of a sensory (cochlear) from a 
neural (retrocochlear) hearing loss is indicated. 

Pure tone audiometry assesses hearing acuity for pure 
tones. The test is administered by an audiologist and is 
performed in a sound-attenuated chamber. The pure 
tone stimulus is delivered with an audiometer, an elec- 
tronic device that allows the presentation of specific fre- 
quencies (generally between 250 and 8000 Hz) at specific 
intensities. Air and bone conduction thresholds are estab- 
lished for each ear. Air conduction thresholds are deter- 
mined by presenting the stimulus in air with the use of 
headphones. Bone conduction thresholds are determined 
by placing the stem of a vibrating tuning fork or an 
oscillator of an audiometer in contact with the head. 
In the presence of a hearing loss, broad-spectrum noise 
is presented to the nontest ear for masking purposes so 
that responses are based on perception from the ear 
under test. 

The responses are measured in decibels. An audiogram is 
a plot of intensity in decibels of hearing threshold versus 
frequency. A decibel (dB) is equal to 20 times the loga- 
rithm of the ratio of the sound pressure required to 
achieve threshold in the patient to the sound pressure 
required to achieve threshold in a normal hearing person. 



Therefore, a change of 6 dB represents doubling of sound 
pressure, and a change of 20 dB represents a tenfold 
change in sound pressure. Loudness, which depends on 
the frequency, intensity, and duration of a sound, doubles 
with approximately each 10-dB increase in sound pres- 
sure level. Pitch, on the other hand, does not directly cor- 
relate with frequency. The perception of pitch changes 
slowly in the low and high frequencies. In the middle 
tones, which are important for human speech, pitch varies 
more rapidly with changes in frequency. 

Pure tone audiometry establishes the presence and 
severity of hearing impairment, unilateral vs. bilateral 
involvement, and the type of hearing loss. Conductive 
hearing losses with a large mass component, as is often 
seen in middle-ear effusions, produce elevation of 
thresholds that predominate in the higher frequencies. 
Conductive hearing losses with a large stiffness compo- 
nent, as in fixation of the footplate of the stapes in early 
otosclerosis, produce threshold elevations in the lower 
frequencies. Often, the conductive hearing loss involves 
all frequencies, suggesting involvement of both stiffness 
and mass. In general, sensorineural hearing losses such as 
presbycusis affect higher frequencies more than lower 
frequencies. An exception is Meniere's disease, which is 
characteristically associated with low-frequency sen- 
sorineural hearing loss. Noise-induced hearing loss has 
an unusual pattern of hearing impairment in which the 
loss at 4000 Hz is greater than at higher frequencies. 
Vestibular schwannomas characteristically affect the 
higher frequencies, but any pattern of hearing loss can 
be observed. 

Speech recognition requires greater synchronous 
neural firing than is necessary for appreciation of pure 
tones. Speech audiometry tests the clarity with which one 
hears. The speech reception threshold (SRT) is defined as 
the intensity at which speech is recognized as a mean- 
ingful symbol and is obtained by presenting two-syllable 
words with an equal accent on each syllable. The inten- 
sity at which the patient can repeat 50% of the words 
correctly is the SRT. Once the SRT is determined, dis- 
crimination or word recognition ability is tested by pre- 
senting one-syllable words at 25-40 dB above the SRT. 
The words are phonetically balanced in that the 
phonemes (speech sounds) occur in the list of words at 
the same frequency that they occur in ordinary conver- 
sational English. An individual with normal hearing 
or conductive hearing loss can repeat 88—100% of the 
phonetically balanced words correctly. Patients with a 
sensorineural hearing loss have variable loss of discrimi- 
nation. As a general rule, neural lesions produce greater 
deficits in discrimination than do lesions in the inner 
ear. For example, in a patient with mild asymmetric sen- 
sorineural hearing loss, a clue to the diagnosis of 
vestibular schwannoma is the presence of a substantial 
deterioration in discrimination ability. Deterioration in 
discrimination ability at higher intensities above the 



SRT also suggests a lesion in the eighth nerve or central 
auditory pathways. 

Tympanometry measures the impedance of the middle 
ear to sound and is useful in diagnosis of middle-ear 
effusions. A tympanogram is the graphic representation of 
change in impedance or compliance as the pressure in 
the ear canal is changed. Normally, the middle ear is 
most compliant at atmospheric pressure, and the com- 
pliance decreases as the pressure is increased or 
decreased; this pattern is seen with normal hearing or in 
the presence of sensorineural hearing loss. Compliance 
that does not change with change in pressure suggests 
middle-ear effusion. With a negative pressure in the 
middle ear, as with eustachian tube obstruction, the 
point of maximal compliance occurs with negative pres- 
sure in the ear canal. A tympanogram in which no point 
of maximal compliance can be obtained is most com- 
monly seen with discontinuity of the ossicular chain. A 
reduction in the maximal compliance peak can be seen 
in otosclerosis. 

During tympanometry, an intense tone elicits con- 
traction of the stapedius muscle. The change in compli- 
ance of the middle ear with contraction of the stapedius 
muscle can be detected. The presence or absence of this 
acoustic reflex is important in the anatomic localization of 
facial nerve paralysis as well as hearing loss. Normal or 
elevated acoustic reflex threshold in an individual with 
sensorineural hearing impairment suggests a cochlear 
hearing loss. Assessment of acoustic reflex decay helps dif- 
ferentiate sensory from neural hearing losses. In neural 
hearing loss, the reflex adapts or decays with time. 

Otoacoustic emissions (OAE) can be measured -with 
microphones inserted into the external auditory canal. 
The emissions may be spontaneous or evoked with 
sound stimulation. The presence of OAEs indicates that 
the outer hair cells of the organ of Corti are intact and 
can be used to assess auditory thresholds and to distin- 
guish sensory from neural hearing losses. 

Evoked Responses 

Electrocochleography measures the earliest evoked poten- 
tials generated in the cochlea and the auditory nerve. 
Receptor potentials recorded include the cochlear 
microphonic, generated by the outer hair cells of the 
organ of Corti, and the summating potential, generated 
by the inner hair cells in response to sound. The whole 
nerve action potential representing the composite firing 
of the first-order neurons can also be recorded during 
electrocochleography. Clinically, the test is useful in the 
diagnosis of Meniere's disease, where an elevation of the 
ratio of summating potential to action potential is seen. 
Brainstem auditory evoked responses (BAERs) are useful 
in differentiating the site of sensorineural hearing loss. 
In response to sound, five distinct electrical potentials 
arising from different stations along the peripheral and 



205 






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206 central auditory pathway can be identified using com- 
puter averaging from scalp surface electrodes. BAERs are 
valuable in situations in which patients cannot or will 
not give reliable voluntary thresholds. They are also used 
to assess the integrity of the auditory nerve and brain- 
stem in various clinical situations, including intraopera- 
tive monitoring and in determination of brain death. 

The vestibular-evoked myogenic potential (VEMP) test 
elicits a vestibulocollic reflex whose afferent limb arises 
from acoustically sensitive cells in the saccule, with sig- 
nals conducted via the inferior vestibular nerve. VEMP is 
a biphasic, short-latency response recorded from the ton- 
ically contracted sternocleidomastoid muscle in response 
to loud auditory clicks or tones. VEMPs may be dimin- 
ished or absent in patients with early and late Meniere's 
disease, vestibular neuritis, benign paroxysmal positional 
vertigo, and vestibular schwannoma. On the other hand, 
the threshold for VEMPs may be lower in cases of supe- 
rior canal dehiscence and perilymphatic fistula. 



S. Imaging Studies 

o' 

on The choice of radiologic tests is largely determined by 
2-, whether the goal is to evaluate the bony anatomy of the 
to external, middle, and inner ear or to image the auditory 
3 nerve and brain. Axial and coronal CT of the temporal 
bone with fine 1-mm cuts is ideal for determining the 
caliber of the external auditory canal, integrity of the 
ossicular chain, and presence of middle-ear or mastoid 
disease; it can also detect inner-ear malformations. CT is 
also ideal for the detection of bone erosion with chronic 
otitis media and cholesteatoma. MRI is superior to CT 
for imaging of retrocochlear pathology such as vestibular 
schwannoma, meningioma, other lesions of the cerebel- 
lopontine angle, demyelinating lesions of the brainstem, 
and brain tumors. Both CT and MRI are equally capa- 
ble of identifying inner-ear malformations and assessing 
cochlear patency for preoperative evaluation of patients 
for cochlear implantation. 



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Treatment: 
fy DISORDERS OF THE SENSE 

OF HEARING 

In general, conductive hearing losses are amenable to 
surgical correction, while sensorineural hearing losses 
are more difficult to manage. Atresia of the ear canal can 
be surgically repaired, often with significant improve- 
ment in hearing. Tympanic membrane perforations due 
to chronic otitis media or trauma can be repaired with 
an outpatient tympanoplasty. Likewise, conductive hear- 
ing loss associated with otosclerosis can be treated by 
stapedectomy, which is successful in 90-95% of cases. 



Tympanostomy tubes allow the prompt return of nor- 
mal hearing in individuals with middle-ear effusions. 
Hearing aids are effective and well-tolerated in patients 
with conductive hearing losses. 

Patients with mild, moderate, and severe sen- 
sorineural hearing losses are regularly rehabilitated with 
hearing aids of varying configuration and strength. 
Hearing aids have been improved to provide greater 
fidelity and have been miniaturized.The current genera- 
tion of hearing aids can be placed entirely within the 
ear canal, thus reducing any stigma associated with 
their use. In general, the more severe the hearing 
impairment, the larger the hearing aid required for audi- 
tory rehabilitation. Digital hearing aids lend themselves 
to individual programming, and multiple and direc- 
tional microphones at the ear level may be helpful in 
noisy surroundings. Since all hearing aids amplify noise 
as well as speech, the only absolute solution to the 
problem of noise is to place the microphone closer to 
the speaker than the noise source. This arrangement is 
not possible with a self-contained, cosmetically accept- 
able device. 

In many situations, including lectures and the the- 
ater, hearing-impaired persons benefit from assistive 
devices that are based on the principle of having the 
speaker closer to the microphone than any source of 
noise. Assistive devices include infrared and frequency- 
modulated (FM) transmission as well as an electromag- 
netic loop around the room for transmission to the indi- 
vidual's hearing aid. Hearing aids with telecoils can also 
be used with properly equipped telephones in the 
same way. 

In the event that the hearing aid provides inade- 
quate rehabilitation, cochlear implants may be appro- 
priate. Criteria for implantation include severe to pro- 
found hearing loss with word recognition score < 30% 
under best aided conditions. Worldwide, >20,000 deaf 
individuals (including 4000 children) have received 
cochlear implants. Cochlear implants are neural pros- 
theses that convert sound energy to electrical energy 
and can be used to stimulate the auditory division of 
the eighth nerve directly. In most cases of profound 
hearing impairment, the auditory hair cells are lost but 
the ganglionic cells of the auditory division of the 
eighth nerve are preserved. Cochlear implants consist of 
electrodes that are inserted into the cochlea through 
the round window, speech processors that extract 
acoustical elements of speech for conversion to electri- 
cal currents, and a means of transmitting the electrical 
energy through the skin. Patients with implants experi- 
ence sound that helps with speech reading, allows open- 
set word recognition, and helps in modulating the person's 
own voice. Usually, within 3 months after implanta- 
tion, adult patients can understand speech without 
visual cues. With the current generation of multichannel 



cochlear implants, nearly 75% of patients are able to 
converse on the telephone. For individuals who have 
had both eighth nerves destroyed by trauma or bilateral 
vestibular schwannomas (e.g., neurofibromatosis type 2), 
brainstem auditory implants placed near the cochlear 
nucleus may provide auditory rehabilitation. 

Tinnitus often accompanies hearing loss. As for back- 
ground noise, tinnitus can degrade speech comprehen- 
sion in individuals with hearing impairment.Therapy for 
tinnitus is usually directed toward minimizing the 
appreciation of tinnitus. Relief of the tinnitus may be 
obtained by masking it with background music. Hearing 
aids are also helpful in tinnitus suppression, as are tinni- 
tus maskers, devices that present a sound to the 
affected ear that is more pleasant to listen to than the 
tinnitus. The use of a tinnitus masker is often followed 
by several hours of inhibition of the tinnitus. Antide- 
pressants have been shown to be beneficial in helping 
patients cope with tinnitus. 

Hard-of-hearing individuals often benefit from a 
reduction in unnecessary noise (e.g., radio or television) 
to enhance the signal-to-noise ratio. Speech compre- 
hension is aided by lip reading; therefore the impaired 
listener should be seated so that the face of the speaker 
is well-illuminated and easily seen. Although speech 
should be in a loud, clear voice, one should be aware 
that in sensorineural hearing losses in general and in 
hard-of-hearing elderly in particular, recruitment 
(abnormal perception of loud sounds) may be trouble- 
some. Above all, optimal communication cannot take 
place without both parties giving it their full and undi- 
vided attention. 



PREVENTION 

Conductive hearing losses may be prevented by prompt 
antibiotic therapy of adequate duration for AOM and by 
ventilation of the middle ear with tympanostomy tubes 
in middle-ear effusions lasting >12 weeks. Loss of 
vestibular function and deafness due to aminoglycoside 



antibiotics can largely be prevented by careful monitor- 
ing of serum peak and trough levels. 

Some 10 million Americans have noise-induced hear- 
ing loss, and 20 million are exposed to hazardous noise in 
their employment. Noise-induced hearing loss can be 
prevented by avoidance of exposure to loud noise or by 
regular use of ear plugs or fluid-filled ear muffs to atten- 
uate intense sound. High-risk activities for noise-induced 
hearing loss include wood and metal working with elec- 
trical equipment and target practice and hunting with 
small firearms. All internal-combustion and electric 
engines, including snow and leaf blowers, snowmobiles, 
outboard motors, and chain saws, require protection of 
the user with hearing protectors. Virtually all noise- 
induced hearing loss is preventable through education, 
which should begin before the teenage years. Programs 
of industrial conservation of hearing are required when 
the exposure over an 8-h period averages 85 dB. Workers 
in such noisy environments can be protected with pre- 
employment audiologic assessment, the mandatory use of 
hearing protectors, and annual audiologic assessments. 

Acknowledgment 

The author acknowledges the contributions of Dr. James B. Snow, Jr., 
to this chapter. 



FURTHER READINGS 

BRESLIN PA, HUANG L: Human taste: Peripheral anatomy, taste trans- 
duction, and coding. Adv Otorhinolaryngol 63:152, 2006 

DOTY RL: The olfactory system and its disorders. Semin neurol 
29:74, 2009 

DULAC C: Sparse encoding of natural scents. Neuron 50:816, 2006 

Gates GA, Mills JH: Presbycusis. Lancet 366: 1 1 1 1 , 2005 

HASIN-BRUMSHTEIN Y et al: Human olfaction: from genomic varia- 
tion to phenotypic diversity. Trends Genet. 25:178, 2009 

HECKMANN JG, Lang CJ: Neurological causes of taste disorders. Adv 
Otorhinolaryngol 63:255, 2006 

Katz DB et al: Receptors, circuits, and behaviors: new directions in 
chemical senses. J Neurosci 28:11802, 2008 

LALWANI AK (ed): Current Diagnosis and Treatment in Otolaryngology — 
Head & Neck Surgery, 2d ed. New York, McGraw-Hill, 2007 



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Stephen L Hauser ■ M. Flint Beal 



Neurogenetics 21 

Ion Channels and Channelopathies 21 1 

Neurotransmitters and Neurotransmitter Receptors 21 2 

Signaling Pathways and Gene Transcription 21 3 

Myelin 21 3 

Neurotrophic Factors 21 5 

Stem Cells and Transplantation 21 6 

Cell Death — Excitotoxicity and Apoptosis 21 7 

Protein Aggregation and Neurodegeneration 21 9 

Systems Neuroscience 21 9 

Further Readings 221 



The human nervous system is the organ of conscious- 
ness, cognition, ethics, and behavior; as such, it is the 
most intricate structure known to exist. More than one- 
third of the 23,000 genes encoded in the human genome 
are expressed in the nervous system. Each mature brain is 
composed of 100 billion neurons, several million miles of 
axons and dendrites, and >10 15 synapses. Neurons exist 
within a dense parenchyma of multifunctional glial cells 
that synthesize myelin, preserve homeostasis, and regulate 
immune responses. Measured against this background of 
complexity, the achievements of molecular neuroscience 
have been extraordinary. This chapter reviews selected 
themes in neuroscience that provide a context for under- 
standing fundamental mechanisms underlying neurologic 
disorders. 

NEUROGENETICS 

The landscape of neurology has been transformed by 
modern molecular genetics. More than 350 different 
disease-causing genes have now been identified, and 
>1000 neurologic disorders have been genetically mapped 
to various chromosomal locations. The vast majority of 
these represent highly penetrant mutations that cause rare 
neurologic disorders; alternatively, they represent rare 



monogenic causes of common phenotypes. Examples of 
the latter include mutations of the amyloid precursor 
protein in familial Alzheimer's disease, the microtubule - 
associated protein tau (MAPT) in frontotemporal dementia, 
and OC-synuclein in Parkinson's disease. These discoveries 
have been profoundly important because the mutated 
gene in the familial disorder often encodes a protein that 
is also pathogenetically involved (although not mutated) 
in the typical, sporadic form. The common mechanism 
involves disordered processing and, ultimately, aggregation 
of the protein, leading to cell death (see Protein Aggrega- 
tion and Neurodegeneration, later in the chapter). 

There is great optimism that complex genetic disor- 
ders, caused by combinations of both genetic and envi- 
ronmental factors, have now become tractable problems. 
The development of new genetic approaches, such as 
haplotype mapping for the efficient screening of variants 
genome-wide along with advances in high-throughput 
sequencing, are beginning to delineate incompletely 
penetrant genetic variants that influence susceptibility 
to, or modify the expression of, complex diseases includ- 
ing age-related macular degeneration, type 2 diabetes 
mellitus, and Alzheimer's disease. 

Not all genetic diseases of the nervous system are caused 
by simple changes in the linear nucleotide sequence of 



210 



genes. As the complex architecture of the human genome 
becomes better defined, many disorders that result 
from alterations in copy numbers of genes ("gene-dosage" 
effects) resulting from unequal crossing-over are likely to be 
identified. The first copy-number disorders to be recognized 
were Charcot-Marie-Tooth disease type 1A (CMT1A), 
caused by a duplication in the gene encoding the myelin 
protein PMP22, and the reciprocal deletion of the gene 
causing hereditary liability to pressure palsies (HNPP) 
(Chap. 40). Gene-dosage effects are causative in some cases 
of Parkinson's disease (OC-synuclein), Alzheimer's disease 
(amyloid precursor protein), spinal muscular atrophy (sur- 
vival motor neuron 2), the dysmyelinating disorder 
Pelizaeus-Merzbacher syndrome (proteolipid protein 1), 
late-onset leukodystrophy (lamin Bl), and a variety of 
developmental neurologic disorders. It is now evident that 
copy-number variations contribute substantially to normal 
human genomic variation for numerous genes involved in 
neurologic function, regulation of cell growth, and regula- 
tion of metabolism. It is also likely that gene-dosage effects 
will influence many behavioral phenotypes, learning disor- 
ders, and autism spectrum disorders. 

The role of splicing variation as a contributor to neuro- 
logic disease is another area of active investigation. Alterna- 
tive splicing refers to the inclusion of different combinations 
of exons in mature mRNA, resulting in the potential for 
many different protein products encoded by a single gene. 
Alternative splicing represents a powerful mechanism for 
generation of complexity and variation, and this mecha- 
nism appears to be highly prevalent in the nervous system, 
affecting key processes such as neurotransmitter receptors 
and ion channels. Numerous diseases are already known to 
result from abnormalities in alternative splicing. Increased 
inclusion of exon 10-containing transcripts of MAPT can 
cause frontotemporal dementia. Aberrant splicing also 
contributes to the pathogenesis of Duchenne, myotonic, 
and fascioscapulohumeral muscular dystrophies; ataxia 
telangiectasia; neurofibromatosis; some inherited ataxias; 
and fragile X syndrome; among other disorders. It is also 
likely that subtle variations of splicing will influence many 
genetically complex disorders. Recently a splicing variant 
of the interleukin 7 receptor OC chain, resulting in produc- 
tion of more soluble and less membrane -bound receptor, 
was found to be associated with susceptibility to multiple 
sclerosis (MS) in multiple different populations. 

Epigenetics refers to the mechanisms by which levels 
of gene expression can be exquisitely modulated, not by 
variations in the primary genetic sequence of DNA but 
rather by postgenomic alterations in DNA and chro- 
matin structure, which influence how, when, and where 
genes are expressed. DNA methylation, as well as 
methylation and acetylation of histone proteins that 
interact with nuclear DNA to form chromatin, are key 
mediators of these events. Epigenetic processes appear to 
be dynamically active even in postmitotic neurons. 



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Imprinting refers to an epigenetic feature, present for a 211 
subset of genes, in which the predominant expression of 
one allele is determined by its parent-of-origin.The distinc- 
tive neurodevelopmental disorders Prader-Willi syndrome 
(mild mental retardation and endocrine abnormalities) 
and Angelman syndrome (cortical atrophy, cerebellar 
dysmyelination, Purkinje cell loss) are classic examples of 
imprinting disorders whose distinctive features are 
determined by whether the paternal or maternal copy 
of chromosome of the critical genetic region 15qll-13 
was responsible. Preferential allelic expression, whether 
due to imprinting, resistance to X-inactivation, or other 
mechanisms, is likely to play a major role in determining 
complex behaviors and susceptibility to many neuro- 
logic and psychiatric disorders. 



ION CHANNELS AND CHANNELOPATHIES 

The resting potential of neurons and the action poten- 
tials responsible for impulse conduction are generated by 
ion currents and ion channels. Most ion channels are 
gated, meaning that they can transition between confor- 
mations that are open or closed to ion conductance. 
Individual ion channels are distinguished by the specific 
ions they conduct; by their kinetics; and by whether 
they directly sense voltage, are linked to receptors for 
neurotransmitters or other ligands such as neurotrophins, 
or are activated by second messengers. The diverse char- 
acteristics of different ion channels provide a means by 
which neuronal excitability can be exquisitely modu- 
lated at both the cellular and the subcellular levels. Dis- 
orders of ion channels — channelopathies — are responsi- 
ble for a growing list of human neurologic diseases 
(Table 19-1). Most are caused by mutations in ion 
channel genes or by autoantibodies against ion channel 
proteins. One example is epilepsy, a syndrome of diverse 
causes characterized by repetitive, synchronous firing of 
neuronal action potentials. Action potentials are nor- 
mally generated by the opening of sodium channels and 
the inward movement of sodium ions down the intra- 
cellular concentration gradient. Depolarization of 
the neuronal membrane opens potassium channels, 
resulting in outward movement of potassium ions, 
repolarization, closure of the sodium channel, and 
hyperpolarization. Sodium or potassium channel sub- 
unit genes have long been considered candidate dis- 
ease genes in inherited epilepsy syndromes, and recently 
such mutations have been identified. These mutations 
appear to alter the normal gating function of these 
channels, increasing the inherent excitability of neuronal 
membranes in regions where the abnormal channels 
are expressed. 

Whereas the specific clinical manifestations of chan- 
nelopathies are quite variable, one common feature is 



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212 TABLE 19-1 



EXAMPLES OF NEUROLOGIC CHANNELOPATHIES 



QJ 



CATEGORY 


DISORDER 


CHANNEL TYPE 


MUTATED GENE 


CHAP. REF. 


Genetic 


Ataxias 


Episodic ataxia-1 


K 


KCNA1 


26 




Episodic ataxia-2 


Ca 


CACNL1A 






Spinocerebellar ataxia-6 


Ca 


CACNL1A 




Migraine 


Familial hemiplegic migraine 1 


Ca 


CACNL1A 


6 




Familial hemiplegic migraine 2 


Na 


SCN1A 




Epilepsy 


Benign neonatal familial convulsions 










Generalized epilepsy with febrile 


K 


KCNQ2, KCNQ3 


20 




convulsions plus 


Na 


SCN1B 




Periodic paralysis 


Hyperkalemic periodic paralysis 


Na 


SCN4A 


43 




Hypokalemic periodic paralysis 


Ca 


CACNL1A3 




Myotonia 


Myotonia congenita 


CI 


CLCN1 


43 




Paramyotonia congenita 


Na 


SCN4A 




Deafness 


Jorvell and Lange-Nielsen syndrome 
(deafness, prolonged QT interval, 
and arrythmia) 


K 


KCNQ1.KCNE1 


18 




Autosomal dominant progressive deafness 


K 


KCNQ4 




Autoimmune 










Paraneoplastic 


Limbic encephalitis 


Kv1 


— 


39 




Acquired neuromyotonia 


Kv1 


— 


39 




Cerebellar ataxia 


Ca (P/Q type) 


— 


39 




Lambert-Eaton syndrome 


Ca (P/Q type) 


— 


39 



1—1 

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that manifestations tend to be intermittent or paroxys- 
mal, such as occurs in epilepsy, migraine, ataxia, myoto- 
nia, or periodic paralysis. Exceptions are clinically 
progressive channel disorders such as autosomal domi- 
nant hearing impairment. The genetic channelopathies 
identified to date are all uncommon disorders caused by 
obvious mutations in channel genes. As the full reper- 
toire of human ion channels and related proteins is 
identified, it is likely that additional channelopathies will 
be discovered. In addition to rare disorders that result 
from obvious mutations, it is also likely that less pene- 
trant allelic variations in channel genes or in their pat- 
tern of expression might underlie susceptibility to some 
common forms of epilepsy, migraine, or other disorders. 
For example, mutations in the T-type Ca channel gene 
CACNA1H, as well as a K channel (KCND2) and vari- 
ous GABA receptor genes, have been associated with an 
increased risk for epilepsy. 



NEUROTRANSMITTERS AND 
NEUROTRANSMITTER RECEPTORS 

Synaptic neurotransmission is the predominant means by 
which neurons communicate with each other. Classic 
neurotransmitters are synthesized in the presynaptic region 
of the nerve terminal; stored in vesicles; and released into 



the synaptic cleft, where they bind to receptors on the 
postsynaptic cell. Secreted neurotransmitters are elimi- 
nated by reuptake into the presynaptic neuron (or glia), 
by diffusion away from the synaptic cleft, and/or by spe- 
cific inactivation. In addition to the classic neurotransmit- 
ters, many neuropeptides have been identified as definite 
or probable neurotransmitters; these include substance P, 
neurotensin, enkephalins, (3-endorphin, histamine, vasoac- 
tive intestinal polypeptide, cholecystokinin, neuropeptide 
Y, and somatostatin. Peptide neurotransmitters are synthe- 
sized in the cell body rather than the nerve terminal and 
may colocalize with classic neurotransmitters in single 
neurons. Nitric oxide and carbon monoxide are gases that 
appear also to function as neurotransmitters, in part by 
signaling in a retrograde fashion from the postsynaptic to 
the presynaptic cell. 

Neurotransmitters modulate the function of postsy- 
naptic cells by binding to specific neurotransmitter recep- 
tors, of which there are two major types. Ionotropic receptors 
are direct ion channels that open after engagement by the 
neurotransmitter. Metabotropic receptors interact with G 
proteins, stimulating production of second messengers 
and activating protein kinases, which modulate a variety 
of cellular events. Ionotropic receptors are multiple sub- 
unit structures, whereas metabotropic receptors are com- 
posed of single subunits only. One important difference 
between ionotropic and metabotropic receptors is that 



the kinetics of ionotropic receptor effects are fast (gener- 
ally <1 ms) because neurotransmitter binding directly 
alters the electrical properties of the postsynaptic cell, 
whereas metabotropic receptors function over longer 
time periods. These different properties contribute to the 
potential for selective and finely modulated signaling by 
neurotransmitters . 

Neurotransmitter systems are perturbed in a large 
number of clinical disorders, examples of which are high- 
lighted in Tablel9-2. One example is the involvement 
of dopaminergic neurons originating in the substantia 
nigra of the midbrain and projecting to the striatum 
(nigrostriatal pathway) in Parkinson's disease and in heroin 
addicts after the ingestion of the toxin MPTP (1- 
methyl-4- phenyl-1 ,2,5,6-tetrahydropyridine) . 

A second important dopaminergic system arising in 
the midbrain is the mediocorticolimbic pathway, which 
is implicated in the pathogenesis of addictive behaviors 
including drug reward. Its key components include the 
midbrain ventral tegmental area (VTA), median fore- 
brain bundle, and nucleus accumbens (Fig. 48-2). The 
cholinergic pathway originating in the nucleus basalis of 
Meynert plays a role in memory function in Alzheimer's 
disease. 

Addictive drugs share the property of increasing dopamine 
release in the nucleus accumbens. Amphetamine increases 
intracellular release of dopamine from vesicles and 
reverses transport of dopamine through the dopamine 
transporters. Patients prone to addiction show increased 
activation of the nucleus accumbens following adminis- 
tration of amphetamine. Cocaine binds to dopamine trans- 
porters and inhibits dopamine reuptake. Ethanol inhibits 
inhibitory neurons in the VTA, leading to increased 
dopamine release in the nucleus accumbens. Opioids 
also disinhibit these dopaminergic neurons by binding 
to p. receptors expressed by GABA-containing interneu- 
rons in the VTA. Nicotine increases dopamine release by 
activating nicotinic acetylcholine receptors on cell bod- 
ies and nerve terminals of dopaminergic VTA neurons. 
Tetrahydrocannabinol, the active ingredient of cannabis, 
also increases dopamine levels in the nucleus accum- 
bens. Blockade of dopamine in the nucleus accumbens 
can terminate the rewarding effects of addictive drugs. 

Not all cell-to-cell communication in the nervous 
system occurs via neurotransmission. Gap junctions pro- 
vide for direct neuron-neuron electrical conduction and 
also create openings for the diffusion of ions and 
metabolites between cells. In addition to neurons, gap 
junctions are also widespread in glia, creating a syn- 
cytium that protects neurons by removing glutamate and 
potassium from the extracellular environment. Gap junc- 
tions consist of membrane-spanning proteins, termed 
connexins, that pair across adjacent cells. Mechanisms that 
involve gap junctions have been related to a variety of neu- 
rologic disorders. Mutations in connexin 32, a gap junction 
protein expressed by Schwann cells, are responsible for 



the X-linked form of CMT disease (Chap. 40). Muta- 
tions in either of two gap junction proteins expressed in 
the inner ear — connexin 26 and connexin 31 — result in 
autosomal dominant progressive hearing loss (Chap. 18). 
Glial calcium waves mediated through gap junctions also 
appear to explain the phenomenon of spreading depres- 
sion associated with migraine auras and the march of 
epileptic discharges. Spreading depression is a neural 
response that follows a variety of different stimuli and is 
characterized by a circumferentially expanding negative 
potential that propagates at a characteristic speed of 
20 m/s and is associated with an increase in extracellular 
potassium. 



SIGNALING PATHWAYS AND GENE 
TRANSCRIPTION 

The fundamental issue of how memory, learning, and 
thinking are encoded in the nervous system is likely to be 
clarified by identifying the signaling pathways involved in 
neuronal differentiation, axon guidance, and synapse for- 
mation, and by understanding how these pathways are 
modulated by experience. Many families of transcription 
factors, each comprising multiple individual components, 
are expressed in the nervous system. Elucidation of these 
signaling pathways has already begun to provide insights 
into the cause of a variety of neurologic disorders, includ- 
ing inherited disorders of cognition such as X-linked 
mental retardation. This problem affects ~1 in 500 males, 
and linkage studies in different families suggest that as 
many as 60 different X-chromosome encoded genes may 
be responsible. Rett syndrome, a common cause of (domi- 
nant) X-linked progressive mental retardation in females, is 
due to a mutation in a gene (MECP2) encoding a DNA- 
binding protein involved in transcriptional repression. As 
the X chromosome comprises only ~3% of germline 
DNA, then by extrapolation the number of genes that 
potentially contribute to clinical disorders affecting intelli- 
gence in humans must be potentially very large. As dis- 
cussed below, there is increasing evidence that abnormal 
gene transcription may play a role in neurodegenerative 
diseases, such as Huntington's disease, in which proteins 
with polyglutamine expansions bind to and sequester tran- 
scription factors. A critical transcription factor for neuronal 
survival is CREB (cyclic adenosine monophosphate 
responsive element-binding) protein, which also plays an 
important role in memory in the hippocampus. 



MYELIN 

Myelin is the multilayered insulating substance that sur- 
rounds axons and speeds impulse conduction by permit- 
ting action potentials to jump between naked regions of 
axons (nodes of Ranvier) and across myelinated segments. 



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214 TABLE 19-2 



PRINCIPAL CLASSIC NEUROTRANSMITTERS 



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NEUROTRANSMITTER 


ANATOMY 


CLINICAL ASPECTS 


Acetylcholine (ACh) 


Motor neurons in spinal cord — > 


Acetylcholinesterases (nerve gases) 





neuromuscular junction 


Myasthenia gravis (antibodies to ACh 


II 




receptor) 


CH 3 — C— 0— CH 2 — N— (CH 3 ) 3 




Congenital myasthenic syndromes 
(mutations in ACh receptor subunits) 

Lambert-Eaton syndrome (antibodies to 
Ca channels impair ACh release) 

Botulism (toxin disrupts ACh release by 
exocytosis) 




Basal forebrain ^widespread cortex 


Alzheimer's disease (selective cell death) 
Autosomal dominant frontal lobe epilepsy 
(mutations in CNS ACh receptor) 




Interneurons in striatum 


Parkinson's disease (tremor) 




Autonomic nervous system 






(preganglionic and postganglionic 






parasympathetic; preganglionic 






sympathetic) 




Dopamine 


Substantia nigra — > striatum 


Parkinson's disease (selective cell death) 


HO 


(nigrostriatal pathway) 


MPTP parkinsonism (toxin transported into 


)=\ 


Substantia nigra — > limbic system 


neurons) 


HO — / V- CH 2 — CH 2 — NH 3 


and widespread cortex 
Arcuate nucleus of hypothalamus 
— > anterior pituitary (via portal veins) 


Addiction, behavioral disorders 
Inhibits prolactin secretion 


Norepinephrine (NE) 


Locus coeruleus (pons) — > limbic 


Mood disorders (MAOA inhibitors and 


HO 


system, hypothalamus, cortex 


tricyclics increase NE and improve 


)=\ 


Medulla — > locus coeruleus, 


depression) 


HO — / V- CH— CH 2 — NH 2 


spinal cord 


Anxiety 


Postganglionic neurons of 


Orthostatic tachycardia syndrome 


OH 


sympathetic nervous system 


(mutations in NE transporter) 


Serotonin 


Pontine raphe nuclei — > 


Mood disorders (SSRIs improve 


H< ~^ ^\ PH OH Nil 


widespread projections 


depression) 


7**^ Orng Onl2 '"rig 

H 


Medulla/pons — > dorsal horn of 


Migraine pain pathway 


spinal cord 


Pain pathway 


y-Aminobutyric acid (GABA) 


Major inhibitory neurotransmitter in 


Stiff person syndrome (antibodies to 


H 2 N— CH 2 — CH 2 — CH 2 — COOH 


brain; widespread cortical interneurons 


glutamic acid decarboxylase, the 




and long projection pathways 


biosynthetic enzyme for GABA) 
Epilepsy (gabapentin and valproic acid 
increase GABA) 


Glycine 


Major inhibitory neurotransmitter 


Spasticity 


H 2 N— CH 2 — COOH 


in spinal cord 


Hyperekplexia (myoclonic startle syndrome) 
due to mutations in glycine receptor 


Glutamate 


Major excitatory neurotransmitter; 


Seizures due to ingestion of domoic acid 


H 2 N— CH— CH 2 — CH 2 — COOH 


located throughout CNS, including 


(a glutamate analogue) 


1 


cortical pyramidal cells 


Rasmussen's encephalitis (antibody against 


COOH 




glutamate receptor 3) 
Excitotoxic cell death 



Note: CNS, central nervous system; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrariydropyridine; MAOA, monoamine oxidase A; SSRI, selective sero- 
tonin reuptake inhibitor. 



MOG 



PMP22 




215 



FIGURE 19-1 

The molecular architecture of the myelin sheath illustrating 
the most important disease-related proteins. The illustration 
represents a composite of CNS and PNS myelin. Proteins 
restricted to CNS myelin are shown in green, proteins of PNS 
myelin are lavender, and proteins present in both CNS and 
PNS are red. In the CNS, the X-linked allelic disorders, 
Pelizaeus-Merzbacher disease and one variant of familial 
spastic paraplegia, are caused by mutations in the gene for 
proteolipid protein (PLP) that normally promotes extracellular 
compaction between adjacent myelin lamellae. The homo- 
logue of PLP in the PNS is the P protein, mutations in which 
cause the neuropathy Charcot-Marie-Tooth disease (CMT) 
type 1B. The most common form of CMT is the 1A subtype 
caused by a duplication of the PMP22 gene; deletions in 



PMP22 are responsible for another inherited neuropathy 
termed hereditary liability to pressure palsies (Chap. 40). 

In multiple sclerosis (MS), myelin basic protein (MBP) and 
the quantitatively minor CNS protein, myelin oligodendrocyte 
glycoprotein (MOG), are likely T cell and B cell antigens, 
respectively. The location of MOG at the outermost lamella of 
the CNS myelin membrane may facilitate its targeting by 
autoantibodies. In the PNS, autoantibodies against myelin 
gangliosides are implicated in a variety of disorders, includ- 
ing GQ1b in the Fisher variant of Guillain-Barre syndrome, 
GM1 in multifocal motor neuropathy, and sulfatide con- 
stituents of myelin-associated glycoprotein (MAG) in periph- 
eral neuropathies associated with monoclonal gammopathies 
(Chap. 41). 



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Molecular interactions between the myelin membrane 
and axon are required to maintain the stability, function, 
and normal lifespan of both structures. A single oligo- 
dendrocyte usually ensheaths multiple axons in the cen- 
tral nervous system (CNS), whereas in the peripheral 
nervous system (PNS) each Schwann cell typically 
myelinates a single axon. Myelin is a lipid-rich material 
formed by a spiraling process of the membrane of the 
myelinating cell around the axon, creating multiple mem- 
brane bilayers that are tightly apposed (compact myelin) by 
charged protein interactions. Several inhibitors of axon 
growth are expressed on the innermost (periaxonal) 
lamellae of the myelin membrane (see Stem Cells and 
Transplantation, below). A number of clinically impor- 
tant neurologic disorders are caused by inherited muta- 
tions in myelin proteins of the CNS or PNS (Fig. 19-1). 
Constituents of myelin also have a propensity to be tar- 
geted as autoantigens in autoimmune demyelinating dis- 
orders (Fig. 19-2). 



NEUROTROPHIC FACTORS 

Neurotrophic factors (Table 19-3) are secreted proteins 
that modulate neuronal growth, differentiation, repair, 



and survival; some have additional functions, including 
roles in neurotransmission and in the synaptic reorgani- 
zation involved in learning and memory. The neu- 
rotrophin (NT) family contains nerve growth factor 
(NGF), brain-derived neurotrophic factor (BDNF), 
NT3, and NT4/5. The neurotrophins act at TrK and 
p75 receptors to promote survival of neurons. Because 
of their survival-promoting and antiapoptotic effects, 
neurotrophic factors are in theory outstanding candi- 
dates for therapy of disorders characterized by prema- 
ture death of neurons such as occurs in amyotrophic 
lateral sclerosis (ALS) and other degenerative motor 
neuron disorders. Knockout mice lacking receptors for 
ciliary neurotrophic factor (CNTF) or BDNF show loss 
of motor neurons, and experimental motor neuron 
death can be rescued by treatment with various neu- 
rotrophic factors including CNTF, BDNF, and vascular 
endothelial growth factor (VEGF). However, in phase 3 
clinical trials, growth factors were ineffective in human 
ALS. The growth factor glial-derived neurotrophic fac- 
tor (GDNF) is important for survival of dopaminergic 
neurons. It has shown promising neuro restorative effects 
in experimental models of Parkinson's disease and is 
being tested using gene therapy in early-stage human 
clinical trials. 



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Glutamate 

Glycine-(D-series) I 



NMDA receptor 




FIGURE 19-2 

Involvement of mitochondria in cell death. A severe excito- 
toxic insult (fl) results in cell death by necrosis, whereas a 
mild excitotoxic insult (B) results in apoptosis. After a severe 
insult (such as ischemia), there is a large increase in gluta- 
mate activation of NMDA receptors, an increase in intracellu- 
lar Ca 2+ concentrations, activation of nitric oxide synthase 
(NOS), and increased mitochondrial Ca 2+ and superoxide 
generation followed by the formation of ONOO". This sequence 
results in damage to cellular macromolecules including DNA, 
leading to activation of poly-ADP-ribose polymerase (PARS). 
Both mitochondrial accumulation of Ca 2+ and oxidative dam- 
age lead to activation of the permeability transition pore (PTP) 
that is linked to excitotoxic cell death. A mild excitotoxic 



insult can occur due either to an abnormality in an excitotoxi- 
city amino acid receptor, allowing more Ca 2+ flux, or to 
impaired functioning of other ionic channels or of energy pro- 
duction, which may allow the voltage-dependent NMDA 
receptor to be activated by ambient concentrations of gluta- 
mate. This event can then lead to increased mitochondrial 
Ca 2+ and free radical production, yet relatively preserved ATP 
generation. The mitochondria may then release cytochrome c 
(Cytc), caspase 9, apoptosis-inducing factor (AIF), and per- 
haps other mediators that lead to apoptosis. The precise role 
of the PTP in this mode of cell death is still being clarified, 
but there does appear to be involvement of the adenine 
nucleotide transporter that is a key component of the PTP. 



STEM CELLS AND TRANSPLANTATION 

The nervous system is traditionally considered to be a 
nonmitotic organ, in particular with respect to neurons. 
These concepts have been challenged by the finding that 
neural progenitor or stem cells exist in the adult CNS 
that are capable of differentiation, migration over long 
distances, and extensive axonal arborization and synapse 
formation with appropriate targets. These capabilities also 
indicate that the repertoire of factors required for 



growth, survival, differentiation, and migration of these 
cells exists in the mature nervous system. In rodents, 
neural stem cells, defined as progenitor cells capable of 
differentiating into mature cells of neural or glial lineage, 
have been experimentally propagated from fetal CNS 
and neuroectodermal tissues and also from adult germi- 
nal matrix and ependyma regions. Human fetal CNS 
tissue is also capable of differentiation into cells with neu- 
ronal, astrocyte, and oligodendrocyte morphology when 
cultured in the presence of growth factors. Impressively, 



TABLE 19-3 



NEUROTROPHIC FACTORS j 


Neurotrophin family 


Transforming growth factor 


Nerve growth factor 


(3 family 


Brain-derived 


Glial-derived neurotrophic 


neurotrophic factor 


family 


Neurotrophin-3 


Neurturin 


Neurotrophin-4 


Persephin 


Neurotrophin-6 


Fibroblast growth factor 


Cytokine family 


family 


Ciliary neurotrophic factor 


Hepatocyte growth factor 


Leukemia inhibitory factor 


Insulin-like growth factor 


lnterleukin-6 


(IGF) family 


Cardiotrophin-1 


IGF-1 




IGF-2 



such cells could be stably engrafted into mouse CNS tis- 
sue, creating neural chimeras. Another approach is to use 
somatic cell nuclear transfer, in which cell nuclei are placed 
inside an enucleated oocyte and then differentiated into 
stem cells with an identical genetic background to the 
donor. This technique has been utilized successfully in 
animal models of Parkinson's disease. Once the repertoire 
of signals required for cell type specification is better 
understood, differentiation into specific neural or glial 
subpopulations can be directed in vitro; such cells could 
also be engineered to express therapeutic molecules. 
Another promising approach is to utilize growth factors, 
such as BDNF, to stimulate endogenous stem cells to 
proliferate and migrate to areas of neuronal damage. 
Administration of epidermal growth factor with fibrob- 
last growth factor replenished up to 50% of hippocampal 
CA1 neurons a month after global ischemia in rats. The 
new neurons made connections and improved perfor- 
mance in a memory task. 

Although stem cells hold tremendous promise for the 
treatment of debilitating neurologic diseases, such as 
Parkinson's disease and spinal cord injury, it should be 
emphasized that medical application is in its infancy. 
Major obstacles are the generation of position- and 
neurotransmitter-defmed subtypes of neurons and their 
isolation as pure populations of the desired cells. This is 
crucial to avoid persistence of undifferentiated embry- 
onic stem (ES) cells, which can generate tumors. The 
establishment of appropriate neural connections and 
afferent control is also critical. For instance, human ES 
motor neurons will need to be introduced at multiple 
segments in the neuraxis, and then their axons will need 
to regenerate from the spinal cord to distal musculature. 

Experimental transplantation of human fetal dopamin- 
ergic neurons in patients with Parkinson's disease has 
shown that these transplanted cells can survive within the 
host striatum; however, some patients developed disabling 
dyskinesias and this approach is no longer in clinical 



development. Human ES cells can be differentiated into 
dopaminergic neurons, which reverse symptoms of 
Parkinson's disease in experimental animal models. Studies 
of transplantation for patients with Huntington's disease 
have also reported encouraging, although very prelimi- 
nary, results. Oligodendrocyte precursor cells transplanted 
into mice with a dysmyelinating disorder effectively 
migrated in the new environment, interacted with axons, 
and mediated myelination; such experiments raise hope 
that similar transplantation strategies may be feasible in 
human disorders of myelin such as MS. The promise of 
stem cells for treatment of both neurodegenerative dis- 
eases and neural injury is great, but development has 
been slowed by unresolved concerns over safety (includ- 
ing the theoretical risk of malignant transformation of 
transplanted cells), ethics (particularly with respect to use 
of fetal tissue), and efficacy. 

In developing brain, the extracellular matrix provides 
stimulatory and inhibitory signals that promote neuronal 
migration, neurite outgrowth, and axonal extension. 
After neuronal damage, reexpression of inhibitory mole- 
cules such as chondroitin sulfate proteoglycans may pre- 
vent tissue regeneration. Chondroitinase degraded these 
inhibitory molecules and enhanced axonal regeneration 
and motor recovery in a rat model of spinal cord injury. 
Several myelin proteins, specifically Nogo, oligodendro- 
cyte myelin glycoprotein (OMGP), and myelin-associated 
glycoprotein (MAG), may also interfere with axon 
regeneration. Sialidase, which cleaves one class of recep- 
tors for MAG, enhances axonal outgrowth. Antibodies 
against Nogo promote regeneration after experimental 
focal ischemia or spinal cord injury. Nogo, OMGP, and 
MAG all bind to the same neural receptor, the Nogo 
receptor, which mediates its inhibitory function via the 
p75 neurotrophin receptor signaling. 



CELL DEATH -EXCITOTOXICITY 

AND APOPTOSIS 

Excitotoxitity refers to neuronal cell death caused by acti- 
vation of excitatory amino acid receptors (Fig. 19-3). 
Compelling evidence for a role of excitotoxicity, espe- 
cially in ischemic neuronal injury, is derived from exper- 
iments in animal models. Experimental models of stroke 
are associated with increased extracellular concentrations 
of the excitatory amino acid neurotransmitter glutamate, 
and neuronal damage is attenuated by denervation of 
glutamate-containing neurons or the administration of 
glutamate receptor antagonists. The distribution of cells 
sensitive to ischemia corresponds closely with that of 
iV-methyl-D-aspartate (NMDA) receptors (except for cere- 
bellar Purkinje cells, which are vulnerable to hypoxia- 
ischemia but lack NMDA receptors); and competitive 
and noncompetitive NMDA antagonists are effective in 
preventing focal ischemia. In global cerebral ischemia, 



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Holling 



bxtravasation 



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Blood-brain 

barrier 

endothelium 

Astrocytes 

Heat shock 



Activated 
Microglia/ 
macrophages 

Fc receptor 



Brain tissue 




Chemokines 
and cytokines 

Tcell 
activation 



Basal lamina 
Microglia/macrophages 



/ 



Chemokines 
IL-1, IL-12 




Antibody 
complement 



TNF, IFN, free radicals, vasoactive amines, 
complement, proteases, cytokines, eicosanoids 

\ I 

Myelin damage 



FIGURE 19-3 

A model for experimental allergic encephalomyelitis (EAE). 
Crucial steps for disease initiation and progression include 
peripheral activation of preexisting autoreactive T cells; hom- 
ing to the CNS and extravasation across the blood-brain bar- 
rier; reactivation of T cells by exposed autoantigens; secre- 
tion of cytokines; activation of microglia and astrocytes and 



recruitment of a secondary inflammatory wave; and immune- 
mediated myelin destruction. ICAM, intercellular adhesion 
molecule; LFA-1, leukocyte function-associated antigen-1; 
VCAM, vascular cell adhesion molecule; IFN, interferon; IL, 
interleukin; TNF, tumor necrosis factor. 



non-NMDA receptors (kainic acid and AMPA) are acti- 
vated, and antagonists to these receptors are protective. 
Experimental brain damage induced by hypoglycemia is 
also attenuated by NMDA antagonists. 

Excitotoxicity is not a single event but rather a cascade 
of cell injury. Excitotoxicity causes influx of calcium into 
cells, and much of the calcium is sequestered in mito- 
chondria rather than in the cytoplasm. Increased cytoplas- 
mic calcium causes metabolic dysfunction and free radical 
generation; activates protein kinases, phospholipases, nitric 
oxide synthase, proteases, and endonucleases; and inhibits 
protein synthesis. Activation of nitric oxide synthase gen- 
erates nitric oxide (NO*), which can react with superox- 
ide (0» 2 ) to generate peroxynitrite (ONOCT), which 
may play a direct role in neuronal injury. Another critical 
pathway is activation of poly-ADP-ribose polymerase, 
which occurs in response to free radical— mediated DNA 
damage. Experimentally, mice with knockout mutations 
of neuronal nitric oxide synthase or poly-ADP-ribose 



polymerase, or those that overexpress superoxide dismu- 
tase, are resistant to focal ischemia. 

Although excitotoxicity is clearly implicated in the 
pathogenesis of cell death in stroke, to date treatment 
with NMDA antagonists has not proven to be clinically 
useful. Transient receptor potentials (TR.P) are calcium 
channels that are activated by oxidative stress in parallel 
with excitotoxic signal pathways. In addition, glutamate- 
independent pathways of calcium influx via acid-sensing 
ion channels have been identified. These channels trans- 
port calcium in the setting of acidosis and substrate 
depletion, and pharmacologic blockade of these chan- 
nels markedly attenuates stroke injury. These channels 
offer a potential new therapeutic target for stroke. 

Apoptosis, or programmed cell death, plays an impor- 
tant role in both physiologic and pathologic conditions. 
During embryogenesis, apoptotic pathways operate to 
destroy neurons that fail to differentiate appropriately or 
reach their intended targets. There is mounting evidence 



for an increased rate of apoptotic cell death in a variety of 
acute and chronic neurologic diseases. Apoptosis is char- 
acterized by neuronal shrinkage, chromatin condensation, 
and DNA fragmentation, whereas necrotic cell death is 
associated with cytoplasmic and mitochondrial swelling 
followed by dissolution of the cell membrane. Apoptotic 
and necrotic cell death can coexist or be sequential 
events, depending on the severity of the initiating insult. 
Cellular energy reserves appear to have an important role 
in these two forms of cell death, with apoptosis favored 
under conditions in which ATP levels are preserved. Evi- 
dence of DNA fragmentation has been found in a num- 
ber of degenerative neurologic disorders, including 
Alzheimer's disease, Huntington's disease, and ALS. The 
best characterized genetic neurologic disorder related to 
apoptosis is infantile spinal muscular atrophy (Werdnig- 
Hoffmann disease), in which two genes thought to be 
involved in the apoptosis pathways are causative. 

Mitochondria are essential in controlling specific 
apoptosis pathways. The redistribution of cytochrome c, 
as well as apoptosis-inducing factor (AIF), from mito- 
chondria during apoptosis leads to the activation of a 
cascade of intracellular proteases known as caspases. 
Caspase-independent apoptosis occurs after DNA dam- 
age, activation of poly-ADP-ribose polymerase, and 
translocation of AIF into the nucleus. Redistribution of 
cytochrome c is prevented by overproduction of the apop- 
totic protein BCL2 and is promoted by the proapoptotic 
protein BAX. These pathways may be triggered by acti- 
vation of a large pore in the mitochondrial inner mem- 
brane known as the permeability transition pore, although 
in other circumstances they occur independently. 
Recent studies suggest that blocking the mitochondrial 
pore reduces both hypoglycemic and ischemic cell 
death. Mice deficient in cyclophilin D, a key protein 
involved in opening the permeability transition pore, are 
resist